A Pragmatic Biomarker-Driven Algorithm to Guide Antibiotic Use in the Pediatric Intensive Care Unit: The Optimizing Antibiotic Strategies in Sepsis (OASIS) Study.

2016

2016 May 4

2048-7207

<p><strong>BACKGROUND: </strong>Biomarkers that identify critically ill children with systemic inflammatory response syndrome (SIRS) at low risk for bacterial infection may help clinicians reduce unnecessary antibiotic use.</p>

<p><strong>METHODS: </strong>We conducted a prospective cohort study of children with SIRS and suspected infection admitted to a pediatric intensive care unit from January 5, 2012 to March 7, 2014. We enrolled patients upon initiation of new antibiotics (Time 0) and measured a panel of 8 serum biomarkers daily over 72 hours. Microbiology, imaging, and clinical data were reviewed to classify bacterial infections using Centers for Disease Control and Prevention definitions. We identified cut points of biomarker combinations to maximize the negative predictive value (NPV) and specificity for bacterial infection. Excess antibiotics were calculated as days of therapy beyond day 2 after SIRS onset in patients without bacterial infection.</p>

<p><strong>RESULTS: </strong>Infections were identified in 46 of 85 patients: bacterial (n = 22) and viral (24), whereas 39 patients had no infection identified. At Time 0, C-reactive protein (CRP) &lt;5 mg/dL plus serum amyloid A &lt;15.0 µg/mL had an NPV of 0.92 (95% confidence interval [CI], 0.79-1.0) and specificity of 0.54 (95% CI, 0.42-0.66) to identify patients without bacterial infection, whereas CRP &lt;4 mg/dL plus procalcitonin &lt;1.75 ng/mL had an NPV of 0.90 (95% CI, 0.79-1.0) and specificity of 0.43 (95% CI, 0.30-0.55). Patients without bacterial infection received a mean of 3.8 excess days of therapy.</p>

<p><strong>CONCLUSIONS: </strong>Early measurement of select biomarkers can identify children with SIRS in whom antibiotics might be safely discontinued when there is no other objective evidence of infection at 48 hours.</p>

10.1093/jpids/piw023

J Pediatric Infect Dis Soc

27147715

Combined biomarkers discriminate a low likelihood of bacterial infection among surgical intensive care unit patients with suspected sepsis.

2016

2016 Jan 8

1879-0070

<p>Among surgical intensive care unit (SICU) patients, it is difficult to distinguish bacterial sepsis from other causes of systemic inflammatory response syndrome (SIRS). Biomarkers have proven useful to identify the presence of bacterial infection. We enrolled a prospective cohort of 69 SICU patients with suspected sepsis and assayed the concentrations of 9 biomarkers (α-2 macroglobulin [A2M], C-reactive protein, ferritin, fibrinogen, haptoglobin, procalcitonin [PCT], serum amyloid A, serum amyloid P, and tissue plasminogen activator) at baseline, 24, 48, and 72hours. Forty-two patients (61%) had bacterial sepsis by chart review. A2M concentrations were significantly lower, and PCT concentrations were significantly higher in subjects with bacterial sepsis at 3 of 4 time points. Using optimal cutoff values, the combination of baseline A2M and 72-hour PCT achieved a negative predictive value of 75% (95% confidence interval, 54-96%). The combination of A2M and PCT discriminated bacterial sepsis from other SIRS among SICU patients with suspected sepsis.</p>

10.1016/j.diagmicrobio.2016.01.003

Diagn. Microbiol. Infect. Dis.

26971636

Methylphenidate and risk of serious cardiovascular events in adults.

2012

178-85

2012 Feb

1535-7228

<p><strong>OBJECTIVE: </strong>The authors sought to determine whether use of methylphenidate in adults is associated with elevated rates of serious cardiovascular events compared with rates in nonusers.</p>

<p><strong>METHOD: </strong>This was a cohort study of new users of methylphenidate based on administrative data from a five-state Medicaid database and a 14-state commercial insurance database. All new methylphenidate users with at least 180 days of prior enrollment were identified. Users were matched on data source, state, sex, and age to as many as four comparison subjects who did not use methylphenidate, amphetamines, or atomoxetine. A total of 43,999 new methylphenidate users were identified and matched to 175,955 nonusers. Events of primary interest were 1) sudden death or ventricular arrhythmia, 2) stroke, 3) myocardial infarction, and 4) a composite endpoint of stroke or myocardial infarction.</p>

<p><strong>RESULTS: </strong>The age-standardized incidence rate per 1,000 person-years of sudden death or ventricular arrhythmia was 2.17 (95% CI=1.63-2.83) in methylphenidate users and 0.98 (95% CI=0.89-1.08) in nonusers, for an adjusted hazard ratio of 1.84 (95% CI=1.33-2.55). Dosage was inversely associated with risk. Adjusted hazard ratios for stroke, myocardial infarction, and the composite endpoint of stroke or myocardial infarction did not differ statistically from 1.</p>

<p><strong>CONCLUSIONS: </strong>Although initiation of methylphenidate was associated with a 1.8-fold increase in risk of sudden death or ventricular arrhythmia, the lack of a dose-response relationship suggests that this association may not be a causal one.</p>

10.1176/appi.ajp.2011.11010125

Am J Psychiatry

22318795

Amphetamines, atomoxetine and the risk of serious cardiovascular events in adults.

2013

e52991

2013

1932-6203

<p><strong>MAIN OBJECTIVE: </strong>To compare the incidence rates of serious cardiovascular events in adult initiators of amphetamines or atomoxetine to rates in non-users.</p>

<p><strong>METHODS: </strong>This was a retrospective cohort study of new amphetamines (n=38,586) or atomoxetine (n=20,995) users. Each medication user was matched to up to four non-users on age, gender, data source, and state (n=238,183). The following events were primary outcomes of interest 1) sudden death or ventricular arrhythmia, 2) stroke, 3) myocardial infarction, 4) a composite endpoint of stroke or myocardial infarction. Cox proportional hazard regression was used to calculate propensity-adjusted hazard ratios for amphetamines versus matched non-users and atomoxetine versus matched non-users, with intracluster dependence within matched sets accounted for using a robust sandwich estimator.</p>

<p><strong>RESULTS: </strong>The propensity-score adjusted hazard ratio for amphetamines use versus non-use was 1.18 (95% CI: 0.55-2.54) for sudden death/ventricular arrhythmia, 0.80 (95% CI: 0.44-1.47) for stroke, 0.75 (95% CI: 0.42-1.35) for myocardial infarction, and 0.78 (95% CI: 0.51-1.19) for stroke/myocardial infarction. The propensity-score adjusted hazard ratio for atomoxetine use versus non-use was 0.41 (95% CI: 0.10-1.75) for sudden death/ventricular arrhythmia, 1.30 (95% CI: 0.52-3.29) for stroke, 0.56 (95% CI: 0.16-2.00) for myocardial infarction, and 0.92 (95% CI: 0.44-1.92) for stroke/myocardial infarction.</p>

<p><strong>CONCLUSIONS: </strong>Initiation of amphetamines or atomoxetine was not associated with an elevated risk of serious cardiovascular events. However, some of the confidence intervals do not exclude modest elevated risks, e.g. for sudden death/ventricular arrhythmia.</p>

10.1371/journal.pone.0052991

PLoS ONE

23382829

Use of a Combination Biomarker Algorithm To Identify Medical Intensive Care Unit Patients with Suspected Sepsis at Very Low Likelihood of Bacterial Infection.

2015

6494-500

2015 Oct

1098-6596

<p>Sepsis remains a diagnostic challenge in the intensive care unit (ICU), and the use of biomarkers may help in differentiating bacterial sepsis from other causes of systemic inflammatory syndrome (SIRS). The goal of this study was to assess test characteristics of a number of biomarkers for identifying ICU patients with a very low likelihood of bacterial sepsis. A prospective cohort study was conducted in a medical ICU of a university hospital. Immunocompetent patients with presumed bacterial sepsis were consecutively enrolled from January 2012 to May 2013. Concentrations of nine biomarkers (α-2 macroglobulin, C-reactive protein [CRP], ferritin, fibrinogen, haptoglobin, procalcitonin [PCT], serum amyloid A, serum amyloid P, and tissue plasminogen activator) were determined at baseline and at 24 h, 48 h, and 72 h after enrollment. Performance characteristics were calculated for various combinations of biomarkers for discrimination of bacterial sepsis from other causes of SIRS. Seventy patients were included during the study period; 31 (44%) had bacterial sepsis, and 39 (56%) had other causes of SIRS. PCT and CRP values were significantly higher at all measured time points in patients with bacterial sepsis. A number of combinations of PCT and CRP, using various cutoff values and measurement time points, demonstrated high negative predictive values (81.1% to 85.7%) and specificities (63.2% to 79.5%) for diagnosing bacterial sepsis. Combinations of PCT and CRP demonstrated a high ability to discriminate bacterial sepsis from other causes of SIRS in medical ICU patients. Future studies should focus on the use of these algorithms to improve antibiotic use in the ICU setting.</p>

10.1128/AAC.00958-15

Antimicrob. Agents Chemother.

26239984

Comparison of Two Sepsis Recognition Methods in a Pediatric Emergency Department.

2015

1298-306

11/2015

1553-2712

<p><strong>OBJECTIVES: </strong>The objective was to compare the effectiveness of physician judgment and an electronic algorithmic alert to identify pediatric patients with severe sepsis/septic shock in a pediatric emergency department (ED).</p>

<p><strong>METHODS: </strong>This was an observational cohort study of patients older than 56 days with fever or hypothermia. All patients were evaluated for potential sepsis in real time by the ED clinical team. An electronic algorithmic alert was retrospectively applied to identify patients with potential sepsis independent of physician judgment. The primary outcome was the proportion of patients correctly identified with severe sepsis/septic shock defined by consensus criteria. Test characteristics were determined and receiver operating characteristic (ROC) curves were compared.</p>

<p><strong>RESULTS: </strong>Of 19,524 eligible patient visits, 88 patients developed consensus-confirmed severe sepsis or septic shock. Physician judgment identified 159 and the algorithmic alert identified 3,301 patients with potential sepsis. Physician judgment had sensitivity of 72.7% (95% confidence interval [CI] = 72.1% to 73.4%) and specificity of 99.5% (95% CI = 99.4% to 99.6%); the algorithmic alert had sensitivity of 92.1% (95% CI = 91.7% to 92.4%) and specificity of 83.4% (95% CI = 82.9% to 83.9%) for severe sepsis/septic shock. There was no significant difference in the area under the ROC curve for physician judgment (0.86, 95% CI = 0.81 to 0.91) or the algorithm (0.88, 95% CI = 0.85 to 0.91; p = 0.54). A combination method using either positive physician judgment or an algorithmic alert improved sensitivity to 96.6% and specificity to 83.3%. A sequential approach, in which positive identification by the algorithmic alert was then confirmed by physician judgment, achieved 68.2% sensitivity and 99.6% specificity. Positive and negative predictive values for physician judgment versus algorithmic alert were 40.3% versus 2.5% and 99.88% versus 99.96%, respectively.</p>

<p><strong>CONCLUSIONS: </strong>The electronic algorithmic alert was more sensitive but less specific than physician judgment for recognition of pediatric severe sepsis and septic shock. These findings can help to guide institutions in selecting pediatric sepsis recognition methods based on institutional needs and priorities.</p>

10.1111/acem.12814

Acad Emerg Med

26474032

Risk factors for recurrent colonization with methicillin-resistant Staphylococcus aureus in community-dwelling adults and children.

2015

786-93

07/2015

1559-6834

<p>OBJECTIVE To identify risk factors for recurrent methicillin-resistant Staphylococcus aureus (MRSA) colonization. DESIGN Prospective cohort study conducted from January 1, 2010, through December 31, 2012. SETTING Five adult and pediatric academic medical centers. PARTICIPANTS Subjects (ie, index cases) who presented with acute community-onset MRSA skin and soft-tissue infection. METHODS Index cases and all household members performed self-sampling for MRSA colonization every 2 weeks for 6 months. Clearance of colonization was defined as 2 consecutive sampling periods with negative surveillance cultures. Recurrent colonization was defined as any positive MRSA surveillance culture after clearance. Index cases with recurrent MRSA colonization were compared with those without recurrence on the basis of antibiotic exposure, household demographic characteristics, and presence of MRSA colonization in household members. RESULTS The study cohort comprised 195 index cases; recurrent MRSA colonization occurred in 85 (43.6%). Median time to recurrence was 53 days (interquartile range, 36-84 days). Treatment with clindamycin was associated with lower risk of recurrence (odds ratio, 0.52; 95% CI, 0.29-0.93). Higher percentage of household members younger than 18 was associated with increased risk of recurrence (odds ratio, 1.01; 95% CI, 1.00-1.02). The association between MRSA colonization in household members and recurrent colonization in index cases did not reach statistical significance in primary analyses. CONCLUSION A large proportion of patients initially presenting with MRSA skin and soft-tissue infection will have recurrent colonization after clearance. The reduced rate of recurrent colonization associated with clindamycin may indicate a unique role for this antibiotic in the treatment of such infection.</p>

10.1017/ice.2015.76

Infect Control Hosp Epidemiol

25869756

Risk factors for ambulatory urinary tract infections caused by high-MIC fluoroquinolone-susceptible Escherichia coli in women: results from a large case-control study.

2015

1547-51

2015 May

1460-2091

<p><strong>OBJECTIVES: </strong>The prevalence of high-MIC fluoroquinolone-susceptible Escherichia coli (FQSEC) has been increasing. These isolates are one step closer to full fluoroquinolone (FQ) resistance and may lead to delayed response to FQ therapy. Our study aimed to investigate the epidemiology of high-MIC FQSEC in ambulatory urinary tract infections (UTIs).</p>

<p><strong>PATIENTS AND METHODS: </strong>A case-control study was conducted at outpatient services within the University of Pennsylvania Health System, Philadelphia. All female subjects with non-recurrent UTI caused by FQSEC (levofloxacin MIC &lt; 4 mg/L) were enrolled. Cases were subjects with high-MIC FQSEC UTI (levofloxacin MIC &gt;0.12 but &lt; 4 mg/L) and controls were subjects with low-MIC FQSEC UTI (levofloxacin MIC ≤0.12 mg/L). Data on microbiology results and baseline characteristics were extracted from electronic medical records.</p>

<p><strong>RESULTS: </strong>During the 3 year study period (May 2008-April 2011), 11 287 episodes of E. coli bacteriuria were identified. The prevalence of FQSEC, FQ-intermediate susceptible E. coli and FQ-resistant E. coli was 75.0%, 0.4% and 24.6%, respectively. A total of 2001 female subjects with FQSEC UTI were enrolled into our study (165 cases and 1836 controls). Independent risk factors for high-MIC FQ susceptibility included Asian race (OR = 2.92; 95% CI = 1.29-6.58; P = 0.02), underlying renal disease (OR = 2.18; 95% CI = 1.15-4.14; P = 0.02) and previous nitrofurantoin exposure (OR = 8.86; 95% CI = 1.95-40.29; P = 0.005).</p>

<p><strong>CONCLUSIONS: </strong>Asian race, underlying renal disease and previous exposure to nitrofurantoin were identified as independent risk factors for high-MIC FQSEC. There may be some factors that are more common in Asians, which may result in the selection of high-MIC FQSEC. Further studies are necessary to explore these findings.</p>

10.1093/jac/dku548

J. Antimicrob. Chemother.

25630645

Duration of Colonization and Determinants of Earlier Clearance of Colonization With Methicillin-Resistant Staphylococcus aureus.

2015

1489-96

05/2015

1537-6591

<p><strong>BACKGROUND: </strong>The duration of colonization and factors associated with clearance of methicillin-resistant Staphylococcus aureus (MRSA) after community-onset MRSA skin and soft-tissue infection (SSTI) remain unclear.</p>

<p><strong>METHODS: </strong>We conducted a prospective cohort study of patients with acute MRSA SSTI presenting to 5 adult and pediatric academic hospitals from 1 January 2010 through 31 December 2012. Index patients and household members performed self-sampling for MRSA colonization every 2 weeks for 6 months. Clearance of colonization was defined as negative MRSA surveillance cultures during 2 consecutive sampling periods. A Cox proportional hazards regression model was developed to identify determinants of clearance of colonization.</p>

<p><strong>RESULTS: </strong>Two hundred forty-three index patients were included. The median duration of MRSA colonization after SSTI diagnosis was 21 days (95% confidence interval [CI], 19-24), and 19.8% never cleared colonization. Treatment of the SSTI with clindamycin was associated with earlier clearance (hazard ratio [HR], 1.72; 95% CI, 1.28-2.30; P &lt; .001). Older age (HR, 0.99; 95% CI, .98-1.00; P = .01) was associated with longer duration of colonization. There was a borderline significant association between increased number of household members colonized with MRSA and later clearance of colonization in the index patient (HR, 0.85; 95% CI, .71-1.01; P = .06).</p>

<p><strong>CONCLUSIONS: </strong>With a systematic, regular sampling protocol, duration of MRSA colonization was noted to be shorter than previously reported, although 19.8% of patients remained colonized at 6 months. The association between clindamycin and shorter duration of colonization after MRSA SSTI suggests a possible role for the antibiotic selected for treatment of MRSA infection.</p>

10.1093/cid/civ075

Clin. Infect. Dis.

25648237