Executive summary: the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.

Evidenced-based guidelines for management of infants and children with community-acquired pneumonia (CAP) were prepared by an expert panel comprising clinicians and investigators representing community pediatrics, public health, and the pediatric specialties of critical care, emergency medicine, hospital medicine, infectious diseases, pulmonology, and surgery. These guidelines are intended for use by primary care and subspecialty providers responsible for the management of otherwise healthy infants and children with CAP in both outpatient and inpatient settings. Site-of-care management, diagnosis, antimicrobial and adjunctive surgical therapy, and prevention are discussed. Areas that warrant future investigations are also highlighted.

The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America.

Evidenced-based guidelines for management of infants and children with community-acquired pneumonia (CAP) were prepared by an expert panel comprising clinicians and investigators representing community pediatrics, public health, and the pediatric specialties of critical care, emergency medicine, hospital medicine, infectious diseases, pulmonology, and surgery. These guidelines are intended for use by primary care and subspecialty providers responsible for the management of otherwise healthy infants and children with CAP in both outpatient and inpatient settings. Site-of-care management, diagnosis, antimicrobial and adjunctive surgical therapy, and prevention are discussed. Areas that warrant future investigations are also highlighted.

Viral coinfections in children with invasive pneumococcal disease.

BACKGROUND: Respiratory viruses contribute to the seasonal pattern of invasive pneumococcal disease (IPD), but the impact of viral coinfections on the clinical characteristics and outcomes of patients with IPD have not been well defined. OBJECTIVE: This study was designed to describe and compare the clinical presentations and outcomes of patients with IPD with or without viral coinfections. DESIGN/METHODS: Retrospective analyses of records of all children treated at Children's Medical Center Dallas (CMCD) for IPD from July 2005 to June 2008. Viral studies included viral direct fluorescent antibody staining and culture. For comparisons, patients were classified in 3 groups: with positive, negative, and no viral studies performed. RESULTS: A total of 129 patients were admitted to CMCD with IPD during the 3 year study; 57% were male. Ages ranged from 2 months to 18 years (median 25 months) and 48% were <2 years. Viral studies were performed in 82 (63%) patients, and 28 (34%) had positive results. The most common viruses isolated were influenza (7, 25%), rhinoviruses (6, 21%), adenoviruses (6, 21%), and RSV (5, 18%). Peaks of positive viral studies occurred in February and November which coincided with the peak numbers of patients admitted with IPD. Of 6 with adenovirus coinfection, 5 were admitted to Pediatric Intensive Care Unit (PICU). The most common pneumococcal serotypes were 19A (41, 32.5%), 7F (14, 11%), and 23A (13, 10.3%). Pneumonia (42%), bacteremia (22%), and meningitis (17%) were the most common clinical syndromes. There were no differences in duration of fever before admission, maximum temperatures during hospitalization and white blood cell counts, duration of fever and hospitalization between patients with positive and negative viral studies, but there was a trend for patient with positive viral studies to be admitted to PICU more frequently and to have longer PICU stay. Three of the 6 patients who died had documented viral coinfections (2 adenovirus, 1 parainfluenza 3), and all 3 had no underlying conditions. The other 3 patients who died had no viral studies performed. Duration of treatment ranged from 1 to -210 days (median 14), with no differences among the groups. CONCLUSIONS: Viral coinfections were common in children with IPD. Future prospective studies should include new PCR assays to characterize better the impact of viral coinfections in the occurrence and outcome of IPD.

Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis.

UNLABELLED: Alternative antimicrobial regimens are needed for treatment of methicillin-resistant Staphylococcus aureus (MRSA)-associated pulmonary exacerbations in children with cystic fibrosis (CF). There are no published pharmacokinetic (PK) and pharmacodynamic (PD) data for linezolid in children with CF. OBJECTIVES: (1) To determine the PK and PD profile of linezolid among children with CF; (2) to characterize the effect of linezolid on MRSA infection; (3) to determine the effect of age and CF transmembrane regulator (CFTR) gene mutations on drug clearance. HYPOTHESES: Linezolid clearance is enhanced in children with CF requiring a higher dosage regimen. Age and CFTR gene mutations affect drug clearance. METHODS: This was a retrospective cohort study; medical records of children with MRSA-associated pulmonary exacerbations treated with linezolid (10 mg/kg/dose IV every 8h) were reviewed. Linezolid peak and trough concentrations in serum were determined by high performance liquid chromatography, PK profiles determined using standard noncompartmental method, and PD indices were evaluated. RESULTS: 10 children (mean +/- SD, 10.2 +/- 5.5 years) received 14 courses of linezolid at 10 +/- 0.4 mg/kg/dose every 8h for 15.4 +/- 3.2 days. Seven had homozygous DeltaF508 CFTR mutation. Peak and trough linezolid concentrations varied widely (range, 8.4-20.5 and 0.1-11.5 mcg/mL respectively). The PK profile of children <10 years differed significantly from older patients (>or=10 years). The PK indices of children with homozygous DeltaF508 differed marginally from those with heterozygous CFTR mutations, but there were too few subjects to allow separation of age and CFTR mutations effect. No patient achieved the target PD ratio of AUC/MIC >80. MRSA persisted in sputum or throat culture after treatment with linezolid. CONCLUSIONS: Additional PK and PD data are needed to optimize linezolid therapy in children with cystic fibrosis; it is likely that higher doses will be needed.

Effect of clarithromycin on cytokines and chemokines in children with an acute exacerbation of recurrent wheezing: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Clarithromycin is postulated to possess immunomodulatory properties in addition to its antimicrobial activity. OBJECTIVE: To evaluate the effect of clarithromycin on serum and nasopharyngeal cytokine and chemokine concentrations in children with an acute exacerbation of recurrent wheezing. METHODS: Children with a history of recurrent wheezing or asthma and who presented with an acute exacerbation of wheezing were enrolled in a double-blind, randomized trial of clarithromycin vs placebo. Concentrations of tumor necrosis factor alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, RANTES, eotaxin, macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, and monocyte chemoattractant protein 1 were measured in serum and/or nasopharyngeal aspirates before, during, and after therapy. Mycoplasma pneumoniae and Chlamydophila pneumoniae infection were evaluated for by polymerase chain reaction and serologic testing. RESULTS: Nasopharyngeal concentrations of TNF-alpha, IL-1beta, and IL-10 were significantly and persistently lower in children treated with clarithromycin compared with placebo. There tended to be a greater effect of clarithromycin on nasopharyngeal cytokine concentrations in patients with evidence of M. pneumoniae or C. pneumoniae infection. No significant differences were detected in serum cytokines for children treated with clarithromycin compared with placebo. CONCLUSION: Clarithromycin therapy reduces mucosal TNF-alpha, IL-1beta, and IL-10 concentrations in children with an acute exacerbation of recurrent wheezing.

Evaluation of LBM415 (NVP PDF-713), a novel peptide deformylase inhibitor, for treatment of experimental Mycoplasma pneumoniae pneumonia.

Mycoplasma pneumoniae is a major cause of community-acquired pneumonia. We evaluated the efficacy of LBM415, a novel peptide deformylase inhibitor antimicrobial agent, for the treatment of M. pneumoniae pneumonia in a mouse model. Eight-week-old BALB/c mice were intranasally inoculated once with 10(7) CFU of M. pneumoniae. Groups of mice were treated with LBM415 (50 mg/kg of body weight) or placebo subcutaneously daily for 13 days, starting 24 h after inoculation. Groups of mice were evaluated at the baseline; at days of treatment 1, 3, 6, and 13; and at 7 days after treatment. The MIC of LBM415 against M. pneumoniae was <0.005 microg/ml. LBM415-treated mice had significantly lower bronchoalveolar lavage fluid M. pneumoniae concentrations than placebo-treated mice on days 6 and 13 of treatment. Compared with placebo treatment, therapy with LBM415 significantly decreased lung histopathology scores at days 3, 6, and 13 of treatment and at 7 days after treatment. Airway obstruction was significantly lower in LBM415-treated mice than in placebo-treated mice on days 1, 3, and 6 of treatment and after 7 days of therapy, while airway hyperresponsiveness was significantly lower only on day 3 of therapy. The bronchoalveolar lavage fluid concentrations of tumor necrosis factor alpha, gamma interferon (IFN-gamma), interleukin-6 (IL-6), IL-12, KC (functional IL-8), monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha, monokine induced by IFN-gamma, and IFN-inducible protein 10 were significantly reduced in LBM415-treated mice compared with the levels in placebo-treated mice. There were no differences in the bronchoalveolar lavage fluid concentrations of granulocyte-macrophage colony-stimulating factor, IL-1beta, IL-2, IL-4, IL-5, and IL-10 between the two groups of mice. LBM415 therapy had beneficial microbiologic, histologic, respiratory, and immunologic effects on acute murine M. pneumoniae pneumonia.

Bacterial meningitis in children.

Microbiologic causes of meningitis include bacteria, viruses, fungi, and parasites. Before routine use of pneumococcal conjugate vaccine, bacterial meningitis affected almost 6000 people every year in the United States, and about half of all cases occurred in children 18 years old or younger. Prompt and accurate diagnosis and adequate treatment of bacterial meningitis in children remains a major challenge, as reflected by the continued high morbidity and case-fatality rates of the disease worldwide. Appropriate use of antibiotics, along with adjunctive therapies, such dexamethasone, has proved helpful in the prevention of neurologic sequelae in children with bacterial meningitis. Better understanding of pathophysiologic mechanisms likely would result in more effective therapies in the future.

Mycoplasma pneumoniae induces host-dependent pulmonary inflammation and airway obstruction in mice.

Respiratory tract infections result in wheezing in a subset of patients. Mycoplasma pneumoniae is a common etiologic agent of acute respiratory infection in children and adults that has been associated with wheezing in 20-40% of individuals. The current study was undertaken to elucidate the host-dependent pulmonary and immunologic response to M. pneumoniae respiratory infection by studying mice with different immunogenetic backgrounds (BALB/c mice versus C57BL/6 mice). After M. pneumoniae infection, only BALB/c mice developed significant airway obstruction (AO) compared with controls. M. pneumoniae-infected BALB/c mice manifested significantly elevated airway hyperresponsiveness (AHR) compared with C57BL/6 mice 4 and 7 d after inoculation as well as BALB/c control mice. Compared with C57BL/6 mice, BALB/c mice developed worse pulmonary inflammation, including greater peribronchial infiltrates. Infected BALB/c mice had significantly higher concentrations of tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-1beta, IL-6, IL-12, KC (functional IL-8), and macrophage inflammatory protein 1alpha in the bronchoalveolar lavage fluid compared with infected C57BL/6 mice. No differences in IL-2, IL-4, IL-5, IL-10, and granulocyte/macrophage colony-stimulating factor concentrations were found. The mice in this study exhibited host-dependent infection-related AO and AHR associated with chemokine and T-helper type (Th)1 pulmonary host response and not Th2 response after M. pneumoniae infection.

Impact of cethromycin (ABT-773) therapy on microbiological, histologic, immunologic, and respiratory indices in a murine model of Mycoplasma pneumoniae lower respiratory infection.

Mycoplasma pneumoniae is a major etiologic agent of acute lower respiratory infections. We evaluated the antimicrobial and immunologic effects of cethromycin (ABT-773), a ketolide antibiotic, for the treatment of M. pneumoniae pneumonia in a mouse model. Eight-week-old BALB/c mice were inoculated intranasally once with 10(6) CFU of M. pneumoniae on day 0. Treatment was started 24 h after inoculation. Groups of mice were treated subcutaneously with cethromycin at 25 mg/kg of body weight or with placebo daily until sacrifice. Five to ten mice per group were evaluated at days 1, 4, 7, and 10 after inoculation. Outcome variables included bronchoalveolar lavage (BAL) for M. pneumoniae quantitative culture and cytokine and chemokine concentration determinations by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-alpha], gamma interferon [IFN-gamma], interleukin-1beta [IL-1beta], IL-2, IL-4, IL-12, granulocyte-macrophage colony-stimulating factor, IL-8, monocyte chemoattractant protein 1 [MCP-1], and macrophage inflammatory protein 1alpha [MIP-1alpha]), histopathologic score of the lungs (HPS), and pulmonary function tests (PFT) using whole-body, unrestrained plethysmography at the baseline and post-methacholine exposure as indicators of airway obstruction (AO) and airway hyperresponsiveness (AHR), respectively. The cethromycin-treated mice had a greater reduction in M. pneumoniae culture titers than placebo-treated mice, reaching statistical significance on days 7 and 10 (P < 0.05). HPS was significantly reduced in cethromycin-treated mice compared with placebo-treated mice on days 4, 7, and 10 (P < 0.05). Cytokine concentrations in BAL samples were reduced in mice that received cethromycin, and the differences were statistically significant for 7 of the 10 cytokines measured (TNF-alpha, IFN-gamma, IL-1beta, IL-8, IL-12, MCP-1, and MIP-1alpha) on day 4 (P < 0.05). PFT values were improved in the cethromycin-treated mice, with AO and AHR significantly reduced on day 4 (P < 0.05). In this mouse model, treatment with cethromycin significantly reduced M. pneumoniae culture titers in BAL samples, cytokine and chemokine concentrations in BAL samples, histologic inflammation in the lungs, and disease severity as defined by AO and AHR.

Antimicrobial and immunologic activities of clarithromycin in a murine model of Mycoplasma pneumoniae-induced pneumonia.

Because macrolide antibiotics are hypothesized to possess immunomodulatory activity independent of their antimicrobial activity, we evaluated the immunomodulatory effect of clarithromycin in a murine model of lung inflammation induced by either live or UV-killed Mycoplasma pneumoniae. BALB/c mice were intranasally inoculated once with live or UV-killed M. pneumoniae. Clarithromycin (25 mg/kg of body weight) or placebo was subcutaneously administered once daily in both groups of mice. In mice infected with live M. pneumoniae, clarithromycin treatment significantly reduced quantitative M. pneumoniae bronchoalveolar lavage (BAL) culture, pulmonary histopathologic scores (HPS), and airway resistance-obstruction (as measured by plethysmography) compared with placebo. Concentrations of tumor necrosis factor alpha, gamma interferon, interleukin-6 (IL-6), mouse KC (functional IL-8), JE/MCP-1, and MIP-1alpha in BAL fluid were also significantly decreased in mice infected with live M. pneumoniae given clarithromycin. In contrast, mice inoculated with UV-killed M. pneumoniae had no significant reduction in HPS, airway resistance-obstruction, or BAL cytokine or chemokine concentrations in response to clarithromycin administration. Clarithromycin therapy demonstrated beneficial effects (microbiologic, histologic, respiratory, and immunologic) on pneumonia in the mice infected with live M. pneumoniae; this was not observed in the mice inoculated with UV-killed M. pneumoniae.

Mycoplasma pneumoniae induces chronic respiratory infection, airway hyperreactivity, and pulmonary inflammation: a murine model of infection-associated chronic reactive airway disease.

Because chronic Mycoplasma pneumoniae respiratory infection is hypothesized to play a role in asthma, the potential of M. pneumoniae to establish chronic respiratory infection with associated pulmonary disease was investigated in a murine model. BALB/c mice were intranasally inoculated once with M. pneumoniae and examined at 109, 150, 245, 368, and 530 days postinoculation. M. pneumoniae was detected in bronchoalveolar lavage fluid by culture or PCR in 70 and 22% of mice at 109 and 530 days postinoculation, respectively. Lung histopathology was normal up to 368 days postinoculation. At 530 days, however, 78% of the mice inoculated with M. pneumoniae demonstrated abnormal histopathology characterized by peribronchial and perivascular mononuclear infiltrates. A mean histopathologic score (HPS) at 530 days of 5.1 was significantly greater (P < 0.01) than that for controls (HPS score of 0). Serum anti-M. pneumoniae immunoglobulin G was detectable in all of the mice inoculated with M. pneumoniae and was inversely correlated with HPS (r = -0.95, P = 0.01) at 530 days postinoculation. Unrestrained whole-body plethysmography measurement of enhanced pause revealed significantly elevated airway methacholine reactivity in M. pneumoniae-inoculated mice compared with that in controls at 245 days (P = 0.03) and increased airway obstruction at 530 days (P = 0.01). Murine M. pneumoniae respiratory infection can lead to chronic pulmonary disease characterized by airway hyperreactivity, airway obstruction, and histologic inflammation.