Evaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panel.

There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.

An open-label, double tympanocentesis study of levofloxacin therapy in children with, or at high risk for, recurrent or persistent acute otitis media.

BACKGROUND: Levofloxacin has excellent activity against common respiratory pathogens and therefore is likely to be effective in treating children with persistent or recurrent otitis media. OBJECTIVE: The objective of this study was to assess the efficacy and safety of levofloxacin treatment in the eradication of bacterial pathogens from the middle ear fluid (MEF) of children with, or at high risk for, persistent or recurrent otitis media. METHODS: An open-label multicenter trial was conducted that involved tympanocentesis at entry and selectively 3 to 5 days after starting levofloxacin (10 mg/kg twice a day for 10 days). RESULTS: : Two hundred five children (80% < or =2 years) were enrolled. One child did not have a confirmed diagnosis of acute otitis media and did not return for follow-up visits. Of the remaining 204 children, 94 (46%) had bilateral infection and 63 (31%) were receiving antimicrobials immediately before entry. One hundred five isolates of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus. pyogenes were recovered in pure or mixed cultures. All isolates were susceptible to levofloxacin. During-treatment bacterial eradication from MEF occurred in 88% (78 of 89) of bacteriologically evaluable patients, including 90% (65 of 72) of children < or =24 months of age. Bacteria initially isolated from MEF were eradicated in 31 of 37 (84%) children infected with S. pneumoniae and in 54 of 54 (100%) children infected with H. influenzae. Overall, clinical success rate after therapy was 94% for the total study population and 92% for the bacteriologically evaluable population. Levofloxacin was well tolerated. Vomiting (4%) was the most common treatment-limiting adverse event. CONCLUSIONS: Levofloxacin was safe and effective in treating and eradicating common bacterial pathogens from MEF in children with, or at risk for, recurrent or persistent otitis media.

Towards early inclusion of children in tuberculosis drugs trials: a consensus statement.

Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.

Recurrent episodes of shock-like syndrome caused by the same strain of vancomycin-resistant Enterococcus faecium in a pediatric patient.

We present the case of a hospitalized pediatric patient with short bowel syndrome who was dependent upon total parenteral nutrition for 17 months. Shortly after admission she became colonized with vancomycin-resistant Enterococcus faecium (VRE) and developed 12 distinct episodes of serious infection associated with it. The course of VRE colonization and infections in this patient was studied through analysis of 40 representative isolates obtained from different sites during distinct episodes of infection. Standard microbiological techniques, automated ribosomal DNA typing, polymerase chain reaction, and pulsed-field gel electrophoresis (PFGE) were used. All isolates except for the one associated with the initial episode of bacteremia were VRE, and were multidrug resistant. The last four episodes of infection were caused by isolates resistant to all tested antibiotics except for intermediate susceptibility to chloramphenicol. The vanA genotype was a source of vancomycin resistance in all VRE isolates. Both ribotyping and PFGE showed two distinct clones of VRE in clinical and stool surveillance isolates: one was associated with clinical illness and the other was not associated with infection. Recurrent VRE infections occur as a consequence of prolonged gastrointestinal colonization. Morbidity is associated with host factors, the presence of co-pathogens, and possibly intrinsically more virulent VRE strain.

Characterization and dynamics of middle ear fluid and nasopharyngeal isolates of Streptococcus pneumoniae from 12 children treated with levofloxacin.

Children who had acute otitis media and were treated with levofloxacin were assessed for the emergence of fluoroquinolone-resistant Streptococcus pneumoniae. Nasopharynx cultures were obtained from patients at the entry to and during levofloxacin therapy. All nasopharynx isolates (n = 59) from 12 children were levofloxacin susceptible without parC/E or gyrA/B mutations. Pneumococcal nasopharynx persistence was not associated with levofloxacin resistance.

Mechanisms of nutrient modulation of the immune response.

Lack of adequate macronutrients or selected micronutrients, especially zinc, selenium, iron, and the antioxidant vitamins, can lead to clinically significant immune deficiency and infections in children. Undernutrition in critical periods of gestation and neonatal maturation and during weaning impairs the development and differentiation of a normal immune system. Infections are both more frequent and more often become chronic in the malnourished child. Recent identification of genetic mechanisms is revealing critical pathways in the gastrointestinal immune response. New studies show that the development of tolerance, control of inflammation, and response to normal mucosal flora are interrelated and linked to specific immune mechanisms. Nutrients act as antioxidants and as cofactors at the level of cytokine regulation. Protein calorie malnutrition and zinc deficiency activate the hypothalamic-pituitary-adrenal axis. Increased circulating levels of glucocorticoids cause thymic atrophy and affect hematopoiesis. Chronic undernutrition and micronutrient deficiency compromise cytokine response and affect immune cell trafficking. The combination of chronic undernutrition and infection further weakens the immune response, leading to altered immune cell populations and a generalized increase in inflammatory mediators. Obesity caused by excess nutrition or excess storage of fats relative to energy expenditure is a form of malnutrition that is increasingly seen in children. Leptin is emerging as a cytokine-like immune regulator that has complex effects in both overnutrition and in the inflammatory response in malnutrition. Because the immune system is immature at birth, malnutrition in childhood might have long-term effects on health.