Community-acquired pneumonia in children: cell-free plasma sequencing for diagnosis and management.

Community-acquired pneumonia (CAP) is a common cause of pediatric hospital admission. Empiric antibiotic therapy for hospitalized children with serious CAP now targets the most likely pathogen(s), including those that may demonstrate significant antibiotic resistance. Cell-free plasma next-generation sequencing (CFPNGS) was first made available for Pediatric Infectious Diseases physicians in June 1, 2017, to supplement standard-of-care diagnostic techniques. A retrospective chart review was performed for children hospitalized with CAP between June 1, 2017, and January 22, 2018, to evaluate the impact of CFPNGS. We identified 15 hospitalized children with CAP without other underlying medical conditions for whom CFPNGS was performed. CFPNGS identified a pathogen in 13 of 15 (86%) children compared with 47% for those using standard culture and PCR-based methods alone. Changes in antibiotic management were made in 7 of 15 (47%) of children as a result of CFPNGS.

Bacterial and viral co-infections complicating severe influenza: Incidence and impact among 507 U.S. patients, 2013-14.

BACKGROUND: Influenza acts synergistically with bacterial co-pathogens. Few studies have described co-infection in a large cohort with severe influenza infection. OBJECTIVES: To describe the spectrum and clinical impact of co-infections. STUDY DESIGN: Retrospective cohort study of patients with severe influenza infection from September 2013 through April 2014 in intensive care units at 33 U.S. hospitals comparing characteristics of cases with and without co-infection in bivariable and multivariable analysis. RESULTS: Of 507 adult and pediatric patients, 114 (22.5%) developed bacterial co-infection and 23 (4.5%) developed viral co-infection. Staphylococcus aureus was the most common cause of co-infection, isolated in 47 (9.3%) patients. Characteristics independently associated with the development of bacterial co-infection of adult patients in a logistic regression model included the absence of cardiovascular disease (OR 0.41 [0.23-0.73], p=0.003), leukocytosis (>11K/µl, OR 3.7 [2.2-6.2], p<0.001; reference: normal WBC 3.5-11K/µl) at ICU admission and a higher ICU admission SOFA score (for each increase by 1 in SOFA score, OR 1.1 [1.0-1.2], p=0.001). Bacterial co-infections (OR 2.2 [1.4-3.6], p=0.001) and viral co-infections (OR 3.1 [1.3-7.4], p=0.010) were both associated with death in bivariable analysis. Patients with a bacterial co-infection had a longer hospital stay, a longer ICU stay and were likely to have had a greater delay in the initiation of antiviral administration than patients without co-infection (p<0.05) in bivariable analysis. CONCLUSIONS: Bacterial co-infections were common, resulted in delay of antiviral therapy and were associated with increased resource allocation and higher mortality.

A Randomized, Prospective Study of Pediatric Patients With Community-acquired Pneumonia Treated With Ceftaroline Versus Ceftriaxone.

BACKGROUND: Community-acquired bacterial pneumonia (CABP) remains a major infection among children, despite the use of pneumococcal vaccination. Ceftaroline fosamil is a broad-spectrum cephalosporin antibiotic with activity against many bacteria, including Streptococcus pneumoniae (both penicillin-nonsusceptible and multidrug-resistant strains) and Staphylococcus aureus (including methicillin-resistant S. aureus). This article describes the safety, tolerability, and effectiveness of ceftaroline fosamil in the treatment of pediatric patients hospitalized with CABP, from a randomized, active-controlled, observer-blinded clinical study (registration number NCT01530763). METHODS: Pediatric patients were stratified into 4 age cohorts and randomized (3:1) to receive either intravenous ceftaroline fosamil or ceftriaxone, with optional oral switch for a total treatment duration of 5-14 days. Enrollment was planned for 160 patients. Data collected included demographics, infection characteristics and pathogens. Treatment-emergent adverse events, clinical outcomes, and microbiologic responses were assessed. RESULTS: Ceftaroline fosamil was well tolerated. Similar percentages of patients in the ceftaroline fosamil (55/121; 45%) and ceftriaxone (18/39; 46%) groups reported treatment-emergent adverse events. Coombs seroconversion was observed in 17% of patients in the ceftaroline fosamil group; however, no evidence of hemolytic anemia or hemolysis was found. No deaths were reported during the study. Ceftaroline fosamil had similar effectiveness to ceftriaxone, with high clinical cure rates at test-of-cure in the modified intent-to-treat population (94/107; 88% and 32/36; 89%, respectively). Three documented S. aureus infections were successfully treated in the ceftaroline group, including one caused by methicillin-resistant S. aureus. CONCLUSIONS: The results of this study suggest that ceftaroline fosamil may be an important treatment option for pediatric patients hospitalized with CABP.

Evolution of Ceftaroline-Resistant Mrsa in a Child with Cystic Fibrosis Following Repeated Antibiotic Exposure.

Ceftaroline is the first ß-lactam antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA). We describe a ceftaroline-resistant MRSA strain, isolated from a girl with cystic fibrosis after 22 ceftaroline treatment courses. MRSA genome sequencing documented a Tyr446Asn alteration in penicillin binding protein 2 that appeared responsible for resistance. Noncompartmental ceftaroline pharmacokinetic evaluation in our patient documented increased clearance and volume of distribution compared with adults.

Safety and Tolerability of Doripenem in Hospitalized Children With Complicated Intra-Abdominal Infection, Complicated Urinary Tract Infections and Pneumonia.

Three multicenter, randomized, controlled studies evaluated doripenem in children 3 months to <18 years of age, with complicated intra-abdominal or urinary tract infections and bacterial pneumonia.In the 66 patients treated with doripenem before early termination of the studies for nonsafety reasons, doripenem was safe and generally well tolerated. Low enrollment limited ability to assess benefits and risks of doripenem in children.

Severe Influenza in 33 US Hospitals, 2013-2014: Complications and Risk Factors for Death in 507 Patients.

BACKGROUND: Influenza A (H1N1) pdm09 became the predominant circulating strain in the United States during the 2013-2014 influenza season. Little is known about the epidemiology of severe influenza during this season. METHODS: A retrospective cohort study of severely ill patients with influenza infection in intensive care units in 33 US hospitals from September 1, 2013, through April 1, 2014, was conducted to determine risk factors for mortality present on intensive care unit admission and to describe patient characteristics, spectrum of disease, management, and outcomes. RESULTS: A total of 444 adults and 63 children were admitted to an intensive care unit in a study hospital; 93 adults (20.9%) and 4 children (6.3%) died. By logistic regression analysis, the following factors were significantly associated with mortality among adult patients: older age (>65 years, odds ratio, 3.1 [95% CI, 1.4-6.9], P=.006 and 50-64 years, 2.5 [1.3-4.9], P=.007; reference age 18-49 years), male sex (1.9 [1.1-3.3], P=.031), history of malignant tumor with chemotherapy administered within the prior 6 months (12.1 [3.9-37.0], P<.001), and a higher Sequential Organ Failure Assessment score (for each increase by 1 in score, 1.3 [1.2-1.4], P<.001). CONCLUSION: Risk factors for death among US patients with severe influenza during the 2013-2014 season, when influenza A (H1N1) pdm09 was the predominant circulating strain type, shifted in the first postpandemic season in which it predominated toward those of a more typical epidemic influenza season.

Acute bacterial osteoarticular infections: eight-year analysis of C-reactive protein for oral step-down therapy.

BACKGROUND: One of the most important decisions in the treatment of osteoarticular infections is the time at which parenteral therapy can be changed to oral therapy. C-reactive protein (CRP) is an acute inflammatory indicator with a half-life of 19 hours and thus can be helpful in assessing the adequacy of therapy for bacterial infections. At our institution, a combination of CRP and clinical findings is used to determine the transition to oral therapy. METHODS: A search of 8 years of electronic records identified children with osteoarticular infections. Only children with culture-positive acute bacterial arthritis (ABA) or acute bacterial osteomyelitis (ABO) were studied further. A primary chart review of demographic and clinical data was conducted, and a secondary chart review of complicated outcomes was performed. RESULTS: Of 194 total patients, complicated outcomes occurred in 40, of which 35 were prolonged therapy. Only 1 microbiologic failure occurred, presumably due to a retained intra-articular fragment of infected bone. CRP was highest initially among patients with simultaneous ABO + ABA and among those with complicated outcomes, and was lower at the transition to oral therapy in the complicated outcome group (1.5 vs 2.1 mg/dL; P = .012). CONCLUSIONS: The combination of clinical findings and CRP is a useful tool to transition children with osteoarticular infections to oral therapy. Complicated outcomes were associated with higher early CRP at diagnosis and lower CRP at the end of parenteral therapy, suggesting that clinicians were more conservative with prolonged initial parenteral therapy in this group.

Genetic structure of community acquired methicillin-resistant Staphylococcus aureus USA300.

BACKGROUND: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a significant bacterial pathogen that poses considerable clinical and public health challenges. The majority of the CA-MRSA disease burden consists of skin and soft tissue infections (SSTI) not associated with significant morbidity; however, CA-MRSA also causes severe, invasive infections resulting in significant morbidity and mortality. The broad range of disease severity may be influenced by bacterial genetic variation. RESULTS: We sequenced the complete genomes of 36 CA-MRSA clinical isolates from the predominant North American community acquired clonal type USA300 (18 SSTI and 18 severe infection-associated isolates). While all 36 isolates shared remarkable genetic similarity, we found greater overall time-dependent sequence diversity among SSTI isolates. In addition, pathway analysis of non-synonymous variations revealed increased sequence diversity in the putative virulence genes of SSTI isolates. CONCLUSIONS: Here we report the first whole genome survey of diverse clinical isolates of the USA300 lineage and describe the evolution of the pathogen over time within a defined geographic area. The results demonstrate the close relatedness of clinically independent CA-MRSA isolates, which carry implications for understanding CA-MRSA epidemiology and combating its spread.

Diagnostic value of immature neutrophils (bands) in the cerebrospinal fluid of children with cerebrospinal fluid pleocytosis.

OBJECTIVE: We evaluated the diagnostic utility of the presence and number of cerebrospinal fluid (CSF) bands in distinguishing bacterial from aseptic meningitis among children with CSF pleocytosis. METHODS: We identified retrospectively a cohort of children 29 days to 19 years of age with CSF pleocytosis (> or =10 x 10(6) leukocytes per L) who were treated in the emergency departments of 8 pediatric centers between January 2001 and June 2004 and whose CSF was evaluated for the presence of bands. We performed bivariate and multivariate analyses to determine the ability of CSF bands to distinguish bacterial from aseptic meningitis. RESULTS: Among 1116 children whose CSF was evaluated for the presence of bands, 48 children (4% of study patients) had bacterial meningitis. Bacterial meningitis, compared with aseptic meningitis, was associated with a greater CSF band proportion (0.03 vs 0.01; difference: 0.02; 95% confidence interval: 0.00-0.04) and CSF absolute band count (392 x 10(6) cells per L vs 3 x 10(6) cells per L; difference: 389 x 10(6) cells per L; 95% confidence interval: -77 x 10(6) cells per L to 855 x 10(6) cells per L). In addition, 29% of patients with bacterial meningitis, compared with 18% of patients with aseptic meningitis, had any bands detected in the CSF. After adjustment for other factors associated with bacterial meningitis, however, CSF band presence, CSF absolute band count, and CSF band proportion were not independently associated with bacterial meningitis. CONCLUSION: In this multicenter study, neither the presence nor quantity of CSF bands independently predicted bacterial meningitis among children with CSF pleocytosis.

Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis.

CONTEXT: Children with cerebrospinal fluid (CSF) pleocytosis are routinely admitted to the hospital and treated with parenteral antibiotics, although few have bacterial meningitis. We previously developed a clinical prediction rule, the Bacterial Meningitis Score, that classifies patients at very low risk of bacterial meningitis if they lack all of the following criteria: positive CSF Gram stain, CSF absolute neutrophil count (ANC) of at least 1000 cells/microL, CSF protein of at least 80 mg/dL, peripheral blood ANC of at least 10,000 cells/microL, and a history of seizure before or at the time of presentation. OBJECTIVE: To validate the Bacterial Meningitis Score in the era of widespread pneumococcal conjugate vaccination. DESIGN, SETTING, AND PATIENTS: A multicenter, retrospective cohort study conducted in emergency departments of 20 US academic medical centers through the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. All children aged 29 days to 19 years who presented at participating emergency departments between January 1, 2001, and June 30, 2004, with CSF pleocytosis (CSF white blood cells > or =10 cells/microL) and who had not received antibiotic treatment before lumbar puncture. MAIN OUTCOME MEASURE: The sensitivity and negative predictive value of the Bacterial Meningitis Score. RESULTS: Among 3295 patients with CSF pleocytosis, 121 (3.7%; 95% confidence interval [CI], 3.1%-4.4%) had bacterial meningitis and 3174 (96.3%; 95% CI, 95.5%-96.9%) had aseptic meningitis. Of the 1714 patients categorized as very low risk for bacterial meningitis by the Bacterial Meningitis Score, only 2 had bacterial meningitis (sensitivity, 98.3%; 95% CI, 94.2%-99.8%; negative predictive value, 99.9%; 95% CI, 99.6%-100%), and both were younger than 2 months old. A total of 2518 patients (80%) with aseptic meningitis were hospitalized. CONCLUSIONS: This large multicenter study validates the Bacterial Meningitis Score prediction rule in the era of conjugate pneumococcal vaccine as an accurate decision support tool. The risk of bacterial meningitis is very low (0.1%) in patients with none of the criteria. The Bacterial Meningitis Score may be helpful to guide clinical decision making for the management of children presenting to emergency departments with CSF pleocytosis.

Efficacy of transdermal ketoprofen for delayed onset muscle soreness.

OBJECTIVE: To determine the efficacy of transdermal ketoprofen in reducing delayed-onset muscle soreness (DOMS), limiting systemic absorption, and improving postexercise function following repetitive muscle contraction. DESIGN: Double-blind, placebo-controlled clinical trial. SETTING: OrthoMed, University of California at San Diego, La Jolla, CA, U.S.A. PARTICIPANTS: Thirty-two healthy males 18 to 35 years old. INTERVENTIONS: Subjects performed a leg extension and flexion exercise program designed to create DOMS in quadriceps muscles. Subjects were randomly assigned to receive any combination of transdermal ketoprofen or placebo cream, applied TID, to their right and left quadriceps. MAIN OUTCOME MEASURES: Subjective measure of DOMS in quadriceps muscles, serum ketoprofen levels, strength index scores (a measure of postexercise function), and adverse reactions were assessed at baseline, 24 hours, and 48 hours. RESULTS: Within-subjects analysis (n = 16) showed a significant reduction in DOMS scores in legs receiving transdermal ketoprofen compared with legs receiving placebo cream (P = 0.002 at 48 hours and 0.000 at 24 and 48 hours combined). Between-subjects analysis (n = 16) showed a marginally significant reduction in DOMS scores at 48 hours (P = 0.05 in right legs and 0.053 in left legs). Systemic absorption was minimal, with serum ketoprofen levels in the ng/mL range. No differences in strength index scores were observed. No adverse reactions were reported. CONCLUSIONS: Transdermal ketoprofen appears to be effective in reducing self-reported DOMS after repetitive muscle contraction, particularly after 48 hours. Systemic absorption of the drug was minimal. Treatment did not appear to have any effect on postexercise function, and there were no reported adverse reactions.