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With resistance on the rise among pneumococcal pathogens, prudent use of antibiotics--and reliance on the narrowest-spectrum agent likely to work--must be accompanied by wider use of the vaccine. Are you doing all you can? [ABSTRACT FROM AUTHOR]

Background: Invasive pneumococcal disease (IPD) continues to be a significant burden in children despite the implementation of two generations of conjugate vaccines. Serotype replacement by nonvaccine serotypes is reported in multiple areas around the world. This study is a continuation of previous studies and describes the incidence, serotype distribution, and antibiotic resistance pattern of Streptococcus pneumoniae serotypes causing IPD at Children's Medical Center Dallas after introduction of 13-valent pneumococcal conjugate vaccine (PCV13)., Methods: Streptococcus pneumoniae isolates from normally sterile sites were collected from January 1, 1999 to June 30, 2014. Demographic and clinical information was extracted for analysis. Incidence of IPD was calculated using inpatient and emergency center admissions to Children's Medical Center of Dallas as the denominator. Isolates were serotyped and penicillin/cefotaxime susceptibilities were determined. Selected nontypeable isolates were further characterized by multilocus sequence typing. A χ2 test and the Cochran-Armitage Trend Test for trend analysis were used to evaluate change in serotype and antibiotic susceptibility patterns over time., Results: Comparison of the different study periods showed a significant reduction in the incidence of IPD in PCV13 era compared with prevaccine era and PCV7 era (P < .05). Children younger than 24 months showed the largest reduction of disease incidence. More than 40% of patients with IPD had a documented comorbidity. Cases of pneumonia continued to decrease in the PCV13 era (P < .002). The most common non-PCV13 serotypes after vaccine introduction were as follows: 23B, 6C, 23A, 9N/L, and 12. Penicillin resistance by meningitis breakpoint decreased significantly in the PCV13 era., Conclusions: After introduction of PCV13 in Dallas, incidence of IPD caused by strains contained in the vaccine and penicillin resistance continued to decrease. Serotype replacement phenomena and persistence of PCV7 serotypes were documented. Patients with comorbidities represented a large percentage of patients with IPD. Concerns for geographic variation in serotype replacement phenomena arise from the present study., (© The Author 2016. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

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.

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.

Objective: Women in the postpartum period are at high risk for complications from influenza. Pharmacokinetic data of oseltamivir phosphate in postpartum women, however, are lacking., Study Design: Seven healthy patients within 48 hours of delivery were recruited. Each woman received 75 mg of oseltamivir phosphate. Plasma and breast milk samples were obtained at times 0, 0.5, 1, 2, 4, 8, 12, and 24 hours after the first dose. The samples were analyzed for oseltamivir and oseltamivir carboxylate levels. Using a noncompartmental model, area under the curve (AUC), maximum concentration (C(max)), time to maximum concentration, and half-life were estimated., Results: Oseltamivir phosphate and oseltamivir carboxylate were found in breast milk, although later and in lower levels than that found in plasma. The C(max) and AUC 0-24 was higher for the active metabolite than for the prodrug in both plasma and breast milk., Conclusion: Oseltamivir carboxylate was present in breast milk but in concentrations significantly lower than considered therapeutic in infants., (Copyright © 2011 Mosby, Inc. All rights reserved.)

The purpose of this study was to determine pharmacokinetic parameters for oseltamivir in all trimesters of pregnancy. Thirty pregnant women, 10 per trimester, who were receiving oseltamivir phosphate (75 mg) were recruited to study first-dose pharmacokinetics. Plasma samples were obtained at 0, 0.5, 1, 2, 4, 8, and 12 hours after the first dose. Samples were analyzed for oseltamivir and oseltamivir carboxylate levels. With the use of a noncompartmental model, we estimated the area-under-the-curve, maximum concentration, time-to-maximum concentration, and half-life. There were no significant differences in the pharmacokinetics of oseltamivir by trimester, except for an increased half-life in the first trimester for oseltamivir phosphate and an increased maximum concentration in the third trimester for oseltamivir carboxylate. The levels of oseltamivir carboxylate that were observed were within the range that was needed to achieve inhibitory concentrations at 50% for pandemic H1N1. The pharmacokinetics of oseltamivir does not change significantly according to trimester of pregnancy., (Copyright © 2011 Mosby, Inc. All rights reserved.)

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.

Background: The heptavalent pneumococcal conjugate vaccine (PCV7) has significantly reduced vaccine-type invasive pneumococcal disease (IPD) in children. An increasing percentage of IPD cases are now caused by nonvaccine serotypes. The purpose of our observational study was to define the epidemiology of pneumococcal disease in Dallas, TX children for 8 years after implementation of PCV7 immunization., Methods: Streptococcus pneumoniae isolates from normally sterile sites were collected at Children's Medical Center of Dallas from January 1, 1999 to December 31, 2008. Incidence of IPD was calculated using inpatient and emergency center admissions to Children's Medical Center of Dallas as the denominator. Isolates were serotyped and penicillin and cefotaxime susceptibilities were determined. Serotype 19A isolates were further characterized by multilocus sequence typing., Results: Compared with the prevaccine period of 1999-2000, there was a significant reduction in the incidence of IPD from 2002 to 2008 (P < 0.05), although a significant increase in IPD incidence was observed from 2006 to 2008 (P = 0.038). The number of IPD cases caused by serotype 19A increased from 1999 to 2008 (P < 0.001). There were significant increases in penicillin and cefotaxime nonsusceptible 19A isolates during this 10-year period (P < 0.001 and P = 0.004, respectively). The most common sequence type (ST) of the 19A isolates was ST-199 (42.7%). Clonal complex (cc-156) and cc-320 emerged in the period of 2005-2008 as penicillin and cefotaxime resistant 19A strains., Conclusions: In Dallas, PCV7 immunization reduced significantly the incidence of IPD caused by vaccine-type strains. A significant increase in IPD caused by serotype 19A was observed. The penicillin and cefotaxime nonsusceptible STs, not previously identified in Dallas, have recently become an important cause of IPD.

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., ((c) 2009 Wiley-Liss, Inc.)

Background: Clinical improvement is often delayed among children with invasive infections caused by multidrug resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) despite use of standard antimicrobial therapy. Daptomycin, a bactericidal lipopeptide antibiotic, may prove useful for treatment of these infections in children, but clinical experience is lacking., Methods: Retrospective review of medical records of hospitalized children who received daptomycin for treatment of invasive Gram-positive bacterial infections at Children's Medical Center Dallas from December 2003 to March 2007. Bacterial isolates were tested for susceptibility to daptomycin and characterized by pulsed-field gel electrophoresis and polymerase chain reaction for staphylococcal cassette chromosome mec A., Results: Sixteen children (10 male; median age, 6.5 years) received daptomycin. Fifteen (94%) children had invasive staphylococcal disease (14, MRSA, of which 13 were community-associated; 1, methicillin-susceptible S. aureus), and 1 had urinary tract infection caused by VRE. Twelve children with disseminated staphylococcal disease had bacteremia for 2-10 days despite therapy with 2 or more of the following: vancomycin, clindamycin, rifampin, aminoglycoside, or linezolid. The addition of daptomycin resulted in bacteriologic cure in 6 of 7 evaluable patients with persistent bacteremia. No adverse events were attributed to daptomycin. Overall, 14 patients improved and were discharged home, and 2 died of complications of their underlying medical conditions., Conclusions: The majority of patients demonstrated clinical improvement after addition of daptomycin to conventional antimicrobial therapy. Further studies are needed to assess the pharmacokinetics, pharmacodynamics, safety, and effectiveness of daptomycin in infants and children.

Background: Because the heptavalent pneumococcal conjugate vaccine has reduced vaccine-type invasive pneumococcal disease (IPD) in children, a greater proportion of IPD is now caused by nonvaccine (NVT) serotypes. We analyzed the serotypes, antimicrobial resistance profiles and genetic relatedness of Streptococcus pneumoniae responsible for IPD at Children's Medical Center of Dallas., Methods: S. pneumoniae isolates were collected from January 1, 1999 through December 31, 2005. Incidence of IPD was calculated using inpatient and emergency center admissions to Children's Medical Center of Dallas as the denominator. Isolates were serotyped, and their penicillin and cefotaxime susceptibility determined. The 19A isolates were further characterized by pulsed-field gel electrophoresis, multilocus sequence typing and determination of penicillin-binding proteins and mef and erm genes., Results: The incidence of IPD decreased from 93.6 cases/100,000 patients in 1999 to a nadir of 41 cases/100,000 patients in 2003 (P < 0.001). The number of IPD cases caused by serotype 19A increased, accounting for 40% of the cases of IPD in 2005. Penicillin and cefotaxime susceptibility of IPD isolates did not change from 1999 through 2005 (P = 0.687). There was a decrease in penicillin (P < 0.001) and cefotaxime (P = 0.034) susceptibility in NVT serotypes from 1999 to 2005. Molecular characterization of 19A isolates revealed a predominance of ST-199 (62%). Several highly penicillin-resistant and intermediately cefotaxime-resistant strains emerged in 2004 and 2005., Conclusions: In Dallas, heptavalent pneumococcal conjugate vaccine reduced the incidence of IPD from 1999 to 2005 by reducing the incidence of vaccine-type disease. NVT serotypes, particularly 19A, were prevalent and more resistant to antimicrobials in 2004 and 2005.

Background: Of several oral cephalosporins, cefdinir is recommended as an alternative therapy for children with acute otitis media who have type 1 hypersensitivity to beta-lactams. Because the current cefdinir dosage of 14 mg/kg/d is approved for treatment of acute otitis media caused by penicillin-susceptible Streptococcus pneumoniae, we hypothesized that a 25-mg/kg dose given daily would be more effective for nonsusceptible S. pneumoniae., Methods: We performed pharmacokinetic analyses on 37 infants and children who were given cefdinir in dosages of 14 or 25 mg/kg once daily for 10 days, for the treatment of respiratory and skin or skin structure infections. Cefdinir plasma concentrations were determined with validated liquid chromatology, and pharmacokinetics and pharmacodynamics were determined in relation to the minimum inhibitory concentration values of S. pneumoniae., Results: The maximal plasma concentrations and area-under-the-curve values were significantly higher after the 25-mg/kg in relation to the minimum inhibitory concentration values for S. pneumoniae strains. The pharmacodynamics measure of bacteriologic effectiveness was <40% of the dosing interval (ie, 24 hours), indicating that many of the penicillin-nonsusceptible S. pneumoniae causing acute otitis media would not be effectively treated. Diarrhea occurred in 20% of the 39 subjects that received the larger dosage of cefdinir., Conclusion: A cefdinir dosage of 25 mg/kg daily would be ineffective for treatment of acute otitis media caused by penicillin-nonsusceptible S. pneumoniae strain.

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.

We evaluated the efficacy of azithromycin therapy given as a single high dose or divided over 5 days for the treatment of mild experimental Mycoplasma pneumoniae pneumonia. Although both azithromycin regimens significantly reduced quantitative cultures, lung histopathology, and pulmonary cytokines and chemokines, there were no significant differences between the two regimens.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection occurs commonly in children. Clindamycin resistance may be inducible or constitutive, and the rates of inducible resistance in CA-MRSA that could produce clindamycin treatment failures vary worldwide. The double-disk test was performed in 197 erythromycin-resistant and clindamycin-susceptible CA-MRSA strains from children in Dallas, Texas, from 1999 to 2002 to determine inducible clindamycin resistance. Resistance mechanisms were studied by PCR; epidemiologic trends were studied by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Inducible resistance was demonstrated in 28 (93%+/-6%) of 30 tested isolates in 1999, 21 (64%, +/-11%) of 33 in 2000, 12 (23%+/-7%) of 52 in 2001, and 6 (7%+/-3%) of 82 in 2002. All noninducible strains had the msr(A) gene. Among inducible resistant strains, 31 had erm(B), 24 had erm(C), and 12 had erm(A) genes. Two distinct pulsed types were the most prevalent; one of them was the most common pulsed type in 1999, whereas in 2002 a different pulsed type was prevalent. MLST analyses determined that ST-8 was the most common type, with 76%+/-5% found in 2002. All but one of these clindamycin-susceptible, erythromycin-resistant ST-8 strains showed no induction of clindamycin resistance. We conclude that, among erythromycin-resistant, clindamycin-susceptible CA-MRSA strains isolated from children in Dallas, inducible methylase resistance became less common from 1999 to 2002 (P<0.001). The phenotype of strains was associated with their sequence type. Our results demonstrate a clonal shift in CA-MRSA in Dallas children from 1999 to 2002.

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.

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.

Background: Studies suggest that the 7-valent pneumococcal conjugate vaccine (PCV7) reduces carriage of vaccine-type (VT) Streptococcus pneumoniae (SP). We studied the effect of PCV7 on carriage of VT- and non-VT (NVT) SP, by studying the effect of PCV7 on nasopharyngeal (NP) colonization by VT and NVT SP during early childhood., Methods: At 2 months of age, 278 infants were enrolled in this study. To determine carriage of SP, NP samples were obtained before each PCV7 dose, at 9 months of age, and 2-3 months after the booster dose of vaccine., Results: The carriage of SP increased slightly, from 12% (95% confidence interval [CI], 8%-16%) of subjects at 2 months of age to 18% (95% CI, 13%-23%) at 4 months of age (P<.05). Carriage of SP remained in 24%-30% of subjects during subsequent months. Between the 12- and 18-month visits, the carriage rate of VT SP decreased significantly, from 18% (95% CI, 13%-23%) to 9% (95% CI, 5%-13%) of subjects (P=.001). The trend of a decrease in carriage of penicillin-nonsusceptible SP, from 16% of subjects (95% CI, 11%-21%) at the 12-15-month visit to 9% (95% CI, 5%-13%) at the 15-18-month visit, was found after the booster dose of vaccine., Conclusion: The reduction of VT-SP colonization and replacement by NVT SP after the booster dose of vaccine suggests the possibility that widespread vaccination will result in replacement of pneumococci mainly by antibiotic-susceptible NVT SP.

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.

Objectives: The precise epidemiology of childhood pneumonia remains poorly defined. Accurate and prompt etiologic diagnosis is limited by inadequate clinical, radiologic, and laboratory diagnostic methods. The objective of this study was to determine as precisely as possible the epidemiology and morbidity of community-acquired pneumonia in hospitalized children., Methods: Consecutive immunocompetent children hospitalized with radiographically confirmed lower respiratory infections (LRIs) were evaluated prospectively from January 1999 through March 2000. Positive blood or pleural fluid cultures or pneumolysin-based polymerase chain reaction assays, viral direct fluorescent antibody tests, or viral, mycoplasmal, or chlamydial serologic tests were considered indicative of infection by those organisms. Methods for diagnosis of pneumococcal pneumonia among study subjects were published by us previously. Selected clinical characteristics, indices of inflammation (white blood cell and differential counts and procalcitonin values), and clinical outcome measures (time to defervescence and duration of oxygen supplementation and hospitalization) were compared among groups of children., Results: One hundred fifty-four hospitalized children with LRIs were enrolled. Median age was 33 months (range: 2 months to 17 years). A pathogen was identified in 79% of children. Typical respiratory bacteria were identified in 60% (of which 73% were Streptococcus pneumoniae), viruses in 45%, Mycoplasma pneumoniae in 14%, Chlamydia pneumoniae in 9%, and mixed bacterial/viral infections in 23%. Preschool-aged children had as many episodes of atypical bacterial LRIs as older children. Children with typical bacterial or mixed bacterial/viral infections had the greatest inflammation and disease severity. Multivariate logistic-regression analyses revealed that high temperature (> or = 38.4 degrees C) within 72 hours after admission (odds ratio: 2.2; 95% confidence interval: 1.4-3.5) and the presence of pleural effusion (odds ratio: 6.6; 95% confidence interval: 2.1-21.2) were significantly associated with bacterial pneumonia., Conclusions: This study used an expanded diagnostic armamentarium to define the broad spectrum of pathogens that cause pneumonia in hospitalized children. The data confirm the importance of S pneumoniae and the frequent occurrence of bacterial and viral coinfections in children with pneumonia. These findings will facilitate age-appropriate antibiotic selection and future evaluation of the clinical effectiveness of the pneumococcal conjugate vaccine as well as other candidate vaccines.

Background: Although the epidemiology of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has been explored in many investigations, management of this emerging infection has not been well-studied. For non-methicillin-resistant Staphylococcus aureus skin and soft tissue abscesses, incision and drainage is generally adequate therapy without the use of antibiotics, but this has not been established for CA-MRSA., Methods: Children presenting to Children's Medical Center of Dallas for management of skin and soft tissue abscesses caused by culture-proved CA-MRSA were prospectively followed. We analyzed data from the initial evaluation and from two follow-up visits that focused on the management and outcome of CA-MRSA infection. Retrospective chart review was performed 2 to 6 months after the initial visit., Results: Sixty-nine children were identified with culture-proved CA-MRSA skin and soft tissue abscess. Treatment consisted of drainage in 96% of patients and wound packing in 65%. All children were treated with antibiotics. Five patients (7%) were prescribed an antibiotic to which their CA-MRSA isolate was susceptible before culture results were known. Four patients (6%) required hospital admission on the first follow-up; none of these patients had received an antibiotic effective against CA-MRSA. A significant predictor of hospitalization was having a lesion initially >5 cm (P = 0.004). Initial ineffective antibiotic therapy was not a significant predictor of hospitalization (P = 1.0). Of the 58 patients initially given an ineffective antibiotic and managed as outpatients, an antibiotic active against CA-MRSA was given to 21 (36%) patients after results of cultures were known. No significant differences in response were observed in those who never received an effective antibiotic than in those who did., Conclusions: Incision and drainage without adjunctive antibiotic therapy was effective management of CA-MRSA skin and soft tissue abscesses with a diameter of <5 cm in immunocompetent children.

Dexamethasone (DXM) interferes with the production of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) and can thereby diminish the secondary inflammatory response that follows initiation of antibacterial therapy. A beneficial effect on the outcome of Haemophilus meningitis in children has been proven, but until recently the effect of DXM therapy in pneumococcal meningitis was uncertain. The aim of the present study was to evaluate factors that might influence the modulatory effect of DXM on the antibiotic-induced inflammatory response in a rabbit model of pneumococcal meningitis. DXM (1 mg/kg) was given intravenously 30 min before or 1 h after administration of a pneumococcal cell wall extract, or the first dose of ampicillin. In meningitis induced by cell wall extract, DXM therapy prevented the increase in cerebrospinal fluid (CSF) leucocyte and lactate concentrations, but only if given 30 min before the cell wall extract. In meningitis caused by live organisms, initiation of ampicillin therapy resulted in an increase in CSF TNF-alpha and lactate concentrations only in animals with initial CSF bacterial concentrations > or =5.6 log10 cfu/mL. In those animals, DXM therapy prevented significant elevations in CSF TNF-alpha [median change -184 pg/mL, -114 pg/mL versus +683 pg/mL with DXM (30 min before or 1 h after ampicillin) versus controls (no DXM), respectively, P=0.02] and lactate concentrations [median change -10.6 mmol/L, -1.5 mmol/L versus +14.3 mmol/L with DXM (30 min before or 1 h after ampicillin) versus controls (no DXM), respectively, P=0.01]. These effects were independent of the timing of DXM administration. In this model of experimental pneumococcal meningitis, an antibiotic-induced secondary inflammatory response in the CSF was demonstrated only in animals with high initial CSF bacterial concentrations (> or =5.6 log10 cfu/mL). These effects were modulated by DXM therapy whether it was given 30 min before or 1 h after the first dose of ampicillin.

The emergence of multidrug-resistant strains of Streptococcus pneumoniae drives the development and evaluation of new antipneumococcal agents, especially for the treatment of bacterial meningitis. The aims of the present study were to assess the antibacterial effectiveness of two new quinolones, garenoxacin (BMS; BMS-284756) and moxifloxacin (MOX) in experimental meningitis caused by a vancomycin (VAN)-tolerant S. pneumoniae strain and to compare the results with those obtained by therapy with VAN and ceftriaxone (CRO) in combination. Meningitis was induced in young male New Zealand White rabbits by intracisternal inoculation of a VAN-tolerant pneumococcal strain (strain Tupelo) from a child with meningitis. Sixteen hours after inoculation, therapy was given by intravenous administration of BMS at 20 mg/kg of body weight, followed 5 h later by administration at a dosage of 10 mg/kg (n = 9 animals) or MOX as two doses of 20 mg/kg every 5 h (n = 8 animals). For comparison, we studied the following groups: (i) animals treated with VAN (20 mg/kg every 5 h, three doses) and CRO (125 mg/kg, one dose) (n = 9), (ii) animals infected with a VAN-tolerant strain but not treated (n = 8), (iii) animals infected with a VAN-tolerant pneumococcus isolated from the nasopharynx of a carrier and treated with BMS (n = 8), and (iv) animals infected with a cephalosporin-resistant type 6B S. pneumoniae strain and treated with BMS (n = 6). The MICs of penicillin, CRO, VAN, BMS, and MOX for the Tupelo strain were 2, 1, 0.5, 0.06, and 0.03 micro g/ml, respectively. The rates of killing of strain Tupelo (the change in the log(10) number of CFU per milliliter per hour) in cerebrospinal fluid at 5 h were -0.70 +/- 0.35, -0.61 +/- 0.44, and -0.49 +/- 0.36 for BMS, MOX, and VAN-CRO, respectively. Therapy with BMS and MOX was as effective as therapy with VAN-CRO against VAN-tolerant pneumococcal meningitis in rabbits.

Prior use of antibiotics is associated with carriage of resistant bacteria. Colonization by Streptococcus pneumoniae, Haemophilus influenzae, nonpneumococcal alpha-hemolytic streptococci (NPAHS), and Staphylococcus aureus was evaluated in children receiving antibiotic therapy for acute otitis media and in untreated, healthy control subjects. Children were randomly assigned to receive either amoxicillin/clavulanate (90 mg/kg per day) or azithromycin. Swabs were obtained before initiating therapy and again 2 weeks and 2 months after initiating therapy. We also obtained swabs from control subjects at the time of enrollment and 2 weeks and 2 months after enrollment. The decrease in the rate of carriage of S. pneumoniae and H. influenzae at 2 weeks was significant only in the amoxicillin/clavulanate group (P<.001 and P=.005, respectively). The rate of nasopharyngeal colonization with NPAHS among treated patients increased from 23% to 39% at 2 months (P=.01). This increase was similar for both treatment groups. These results suggest that the competitive balance between organisms is altered by antibiotic therapy.

The prevalence of otitis media is increasing, which affects health care resource utilization across all segments, including the urgent care setting. One of the greatest challenges in the management of acute otitis media (AOM) is the effective treatment of cases caused by pathogens that are resistant to commonly used antibiotics. Whereas the production of beta-lactamases among strains of Haemophilus influenzae and Moraxella catarrhalis is an important consideration for antimicrobial therapy, the high prevalence of resistance to penicillin and other classes of antibiotics among strains of Streptococcus pneumoniae represents a greater clinical concern. The Centers for Disease Control and Prevention (CDC) recently convened the Drug Resistant S. pneumoniae Therapeutic Working Group to develop evidence-based recommendations for the treatment of AOM in an era of prevalent resistance. The recommendations from this group included amoxicillin as the preferred first-line drug because of the demonstrated activity against penicillin-intermediate and -resistant strains of S. pneumoniae, using higher dosages of up to 90 mg/kg per day in certain settings. For patients in whom initial treatment is unsuccessful after 3 days, the recommended agents included high-dose amoxicillin-clavulanate (for activity against beta-lactamase-producing pathogens), clindamycin, cefuroxime axetil, or 1 to 3 doses of intramuscular ceftriaxone. The principles set forth in these guidelines can assist the therapeutic decisionmaking process for practitioners in the urgent care setting.

Background: Trovafloxacin is a new fluoroquinolone that exhibits good penetration into the central nervous system and excellent antimicrobial activity against common meningeal pathogens, including beta-lactam-resistant pneumococci., Purpose and Design: A multicenter, randomized clinical trial was conducted in children with bacterial meningitis to compare the safety and efficacy of trovafloxacin with that of ceftriaxone with or without vancomycin therapy., Results: A total of 311 patients, ages 3 months to 12 years, were enrolled, of whom 203 were fully evaluable, 108 treated with trovafloxacin and 95 with the conventional regimen. Both groups were comparable with regard to baseline characteristics: age; cerebrospinal fluid findings; use of dexamethasone; history of seizures; and etiologic agents. No significant differences between trovafloxacin and the comparator, respectively, were detected in any of the following outcome measures: clinical success at 5 to 7 weeks after treatment (79% vs. 81%); deaths (2% vs. 3%); seizures after enrollment (22% vs. 21%); and severe sequelae (14% vs. 14%). Only 4 of 284 children developed joint abnormalities up to 6 months after treatment, 1 (0.9%) child received trovafloxacin and 3 (3.1%) received the comparator regimen. None of the evaluable patients experienced significant abnormalities of liver function during treatment. One nonevaluable patient who received trovafloxacin for 5 days and ceftriaxone for 11 days was readmitted to the hospital with hepatitis of unknown etiology 1 day after discharge. The episode resolved with liver function tests returning to normal within 2 months., Conclusions: We conclude that trovafloxacin is an effective antibiotic for treatment of pediatric bacterial meningitis. These favorable results support further evaluation of fluoroquinolone therapy for children with meningitis or other serious bacterial infections.

A prospective study of 154 consecutive high-risk hospitalized children with lower respiratory infections was conducted to determine the clinical utility of a pneumolysin-based polymerase chain reaction (PCR) assay compared with blood and pleural fluid cultures and serological and urinary antigen tests to determine the incidence of Streptococcus pneumoniae. Whole blood, buffy coat, or plasma samples from 67 children (44%) tested positive by PCR. Sensitivity was 100% among 11 promptly tested culture-confirmed children and specificity was 95% among control subjects. Age, prior oral antibiotic therapy, and pneumococcal nasopharyngeal colonization did not influence PCR results, whereas several surrogates of disease severity were associated with positive tests. Although serological and urinary antigen tests had comparable sensitivity, specificity varied among infected children, and statistical agreement among all assays was limited. These findings support the use of PCR tests to evaluate the protective efficacy of pneumococcal conjugate vaccines and to identify promptly children with pretreated or nonbacteremic pneumococcal lower respiratory infections.

BMS-284756 is a novel des-fluoro(6) quinolone with a broad antimicrobial activity, including Streptococcus pneumoniae. The purpose of this study was to evaluate the pharmacodynamic profile and effectiveness of BMS-284756 for therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant S. pneumoniae (CRSP). Meningitis was induced in rabbits by intracisternal inoculation of CRSP. BMS-284756 was given intravenously 16 h after intracisternal inoculation in single doses of 2.5 (n = 5 animals), 5 (n = 6), 10 (n = 6), 20 (n = 8), and 30 mg/kg (n = 6), in two doses of 10 mg/kg each separated by 5 h (n = 4), and as a 20-mg/kg dose followed 5 h later by 10 mg/kg (n = 5). The MICs and MBCs of BMS-284756, ceftriaxone, and vancomycin were 0.06 and 0.06, 4 and 4, and 0.25 and 0.25 microg/ml, respectively. After single doses of 10, 20, and 30 mg/kg, the maximum concentrations in cerebrospinal fluid (CSF) (mean +/- standard deviation) were 0.32 +/- 0.12, 0.81 +/- 0.38, and 1.08 +/- 0.43 microg/ml, respectively; the elimination half-life in CSF was 4.5 to 6.3 h. The CSF bacterial killing rates (BKR) at 5 h of the single-dose regimens of 10, 20 and 30 mg/kg were -0.84 +/- 0.48, -1.09 +/- 0.32, and -1.35 +/- 0.05 Deltalog(10) CFU/ml/h. The BKR(0-5) of the divided regimens (10 mg/kg twice and 20 mg/kg followed by 10 mg/kg) was -0.82 +/- 0.52 and -1.24 +/- 0.34 Deltalog(10) CFU/ml/h, respectively. The BKR(0-5) of the combined therapy with vancomycin and ceftriaxone was -1.09 +/- 0.39 Deltalog(10) CFU/ml/h. The penetration of BMS-284756 into purulent CSF relative to plasma was 14 to 25%. The bactericidal effect of BMS-284756 in CSF was concentration dependent. BMS-284756 at 30 mg/kg as a single or divided dose was as effective as standard therapy with vancomycin and ceftriaxone.

Moxifloxacin, an 8-methoxyquinolone with broad-spectrum activity in vitro, was studied in the rabbit model of Escherichia coli meningitis. The purposes of this study were to evaluate the bactericidal effectiveness and the pharmacodynamic profile of moxifloxacin in cerebrospinal fluid (CSF) and to compare the bactericidal activity with that of ceftriaxone and meropenem therapy. After induction of meningitis, animals were given single doses of 10, 20, and 40 mg/kg or divided-dose regimens of 5, 10, and 20 mg/kg twice, separated by 6 h. After single doses, the penetration of moxifloxacin into purulent CSF, measured as percentage of the area under the concentration-time curve (AUC) in CSF relative to the AUC in plasma, was approximately 50%. After single doses of 10, 20, and 40 mg/kg, the maximum CSF concentration (C(max)) values were 1.8, 4.2, and 4.9 microg/ml, respectively; the AUC values (total drug) were 13.4, 25.4, and 27.1 microg/ml x h, respectively, and the half-life values (t(1/2)) were 6.7, 6.6, and 4.7 h, respectively. The bacterial killing in CSF for moxifloxacin, calculated as the Deltalog(10) CFU per milliliter per hour, at 3, 6, and 12 h after single doses of 10, 20, and 40 mg/kg were -5.70, -6.62, and -7.02; -7.37, -7.37, and -6.87; and -6.62, -6.62, and -6.62, respectively, whereas those of ceftriaxone and meropenem were -4.18, -5.24, and -4.43, and -3.64, -3.59, and -4.12, respectively. The CSF pharmacodynamic indices of AUC/MBC and C(max)/MBC were interrelated (r = 0.81); there was less correlation with T > MBC (r = 0.74). In this model, therapy with moxifloxacin appears to be at least as effective as ceftriaxone and more effective than meropenem therapy in eradicating E. coli from CSF.

Clinical practice guidelines can be indispensable tools for managed care organizations (MCOs) in providing cost-effective treatment of common conditions. Guidelines for acute respiratory tract infections, such as acute otitis media (AOM) and acute sinusitis, can assist clinicians in accurately diagnosing these conditions, in providing treatment rationales, and in reducing the costs associated with inappropriate antibiotic prescriptions. Barriers to the implementation of practice guidelines include negative attitudes clinicians may have about guidelines promoted by MCOs; patient/parent expectations for antibiotic treatment; lack of financial resources, information system resources, and support for implementation; and lack of commitment to patient and provider education on the part of MCOs. MCOs can facilitate the adoption and implementation of guidelines with a systematic approach that involves establishing a guideline review process, gaining the support of providers, selecting outcomes measures, collecting and analyzing outcomes data, and providing feedback to clinicians about the impact of changes in their practices. This systematic approach should be used as part of the process for the National Committee for Quality Assurance accreditation. Evidence-based clinical practice guidelines for AOM and sinusitis have been developed recently by national consortia of infectious disease experts. Adoption of these guidelines can assist in preventing the spread of resistant pathogens.

Background: In the preantibiotic era acute mastoiditis was the most common complication of acute otitis media, often resulting in substantial morbidity and mortality. Since 1989 several investigators have documented an increased frequency of acute mastoiditis in children., Methods: The medical records of all children with a discharge diagnosis of acute mastoiditis, managed at Children's Medical Center, Dallas, TX, from 1983 through 1999 were reviewed., Results: There were 57 cases of acute mastoiditis during the 17-year period of 1983 through 1999 compared with 57 cases in a 25-year period of 1955 through 1979 reported previously at the same institution. The number of cases of acute mastoiditis per 10,000 hospital admissions increased significantly (regression analysis P = 0.003) during the more recent 17 years. From 1993 through 1999 there were 4.5 cases or more per 10,000 admissions each year, whereas from 1983 through 1992, the incidence never exceeded 4.3 cases per 10,000 admissions (P = 0.018). The median age of the patients was 48 months. Twenty-two patients (38.5%) were younger than 24 months; 17 of these were 12 months of age or younger. Twenty-two (38.5%) patients had no history of previous episodes of acute otitis media. Streptococcus pneumoniae was the pathogen most often isolated from the cultures. Complications of mastoiditis occurred in 20 children (35%)., Conclusions: We conclude that acute mastoiditis continues to be a problem in the post antibiotic era. It occurs mainly in young children and can be the first evidence of ear disease.

Background: In view of the recent trend toward monotherapy in the treatment of bacterial infection, we evaluate the clinical efficacy and safety of cefepime vs. ceftazidime for the empiric treatment of febrile episodes in neutropenic pediatric cancer patients., Methods: In a single site, open label study, 104 neutropenic pediatric cancer patients [96% with absolute neutrophil count (ANC) of <500 neutrophils/mm3] with a median age of 6 years were randomized (1:1) to receive either intravenous cefepime or ceftazidime (50 mg/kg/dose every 8 h; < or = 6 g/day) for empiric treatment of fever (temperature >38.0 degrees C occurring at least twice in 24 h, or single >38.5 degrees C). Febrile episodes were classified as either microbiologically or clinically documented infection or fever of unknown origin. Therapy continued until the ANC was > or = 1,000 neutrophils/mm3 or there was an increasing ANC in low risk patients (maximum duration of treatment, 8 weeks). The primary efficacy endpoints assessed were clinical and microbiologic response to assigned drug therapy. Secondary outcome measures were rate of early discontinuation of study drug and use of concomitant antibiotic therapy to modify initial study drug regimen., Results: Of 68 patients who could be evaluated for efficacy, 74% (26 of 35) of cefepime-treated patients and 70% (23 of 33) of ceftazidime-treated patients responded to treatment. The small number of study patients precluded statistical analysis of results. In a modified intent-to-treat analysis, 59% of the patients treated with cefepime and 47% of ceftazidime-treated patients responded to therapy. Cefepime patients developed fewer new infections than ceftazidime patients (9% vs. 21%, respectively) and early discontinuation of study drug therapy occurred slightly more often in the ceftazidime group. Further, the use of concomitant systemic antimicrobial therapy (mostly vancomycin) occurred less often in the cefepime-treated patients, as compared with the ceftazidime group [35% [17 of 49] vs. 44% (24 of 55), respectively]. No deaths or serious adverse events were considered to be related to study therapy. The most frequent adverse event was rash that was moderate in severity, and it occurred equally in both groups., Conclusion: Cefepime appears to be safe and effective compared with ceftazidime for initial empiric therapy of febrile episodes in neutropenic pediatric cancer patients.

An immunocompetent murine model of pneumococcal pneumonia and bacteremia was used to evaluate a PCR assay based on amplification of the pneumolysin gene. Mice were treated with trovafloxacin to determine the decline in sensitivity of PCR as lung bacterial concentrations decreased and blood cultures became sterile. Forty-three mice were studied for up to 120 h after start of antibiotic treatment. PCR of buffy coat specimens was more sensitive than PCR of plasma. Only 21% of animals had a positive blood culture, whereas 77% of PCR buffy coat assays were positive. After 48 h of therapy all blood culture specimens were sterile, whereas buffy coat PCR was positive in 57.8% of specimens. PCR of buffy coat specimens was negative in all mice colonized nasally with Streptococcus pneumoniae and in rabbits with Escherichia coli bacteremia. Our results demonstrate that our PCR technique using buffy coat specimens is highly specific for invasive pneumococcal disease and remains positive in the majority of animals for at least 48 h after start of antibiotic therapy.

The effect of antibiotic therapy on nasopharyngeal colonization by Streptococcus pneumoniae and Haemophilus influenzae was evaluated in children diagnosed with acute otitis media. Children were randomly assigned to receive either amoxicillin/clavulanate or azithromycin therapy, and nasopharyngeal swabs were obtained for culture before and after starting therapy. Amoxicillin/clavulanate therapy eradicated or suppressed all strains of S. pneumoniae susceptible to penicillin, 75% of strains with intermediate resistance, and 40% of strains resistant to penicillin. Azithromycin therapy cleared two-thirds of azithromycin-susceptible strains of S. pneumoniae but none of azithromycin-nonsusceptible strains. Selection for antibiotic-resistant strains in individual children was not observed in children who received amoxicillin/clavulanate therapy but was observed in 2 children who received azithromycin therapy. Carriage of H. influenzae was also reduced by antimicrobial therapy but more so by amoxicillin/clavulanate. Antibiotic therapy does not directly increase the number of resistant strains in the population but, by eradicating susceptible strains, allows greater opportunity for carriage and spread of resistant strains.

Background: This paper describes challenges in etiologic diagnosis and treatment of childhood community-acquired pneumonia and the means of addressing some of them., Microbiological Diagnosis: From about one-third to two-thirds of cases of pneumonia can be attributed to a specific etiology depending on which culture, antigen detection and specialized serologic techniques, some of which are unavailable to clinicians, are used. Results of studies in which microbiologic causes have been sought confirm the importance of Streptococcus pneumoniae as the primary bacterial cause of pneumonia in infants and children. Viral etiologies become less prevalent and mycoplasmal and chlamydial infections become more prevalent with increasing age., Empiric Treatment: Because definitive information about causative pathogens is seldom available, treatment of pneumonia is most often empiric. Antibiotic therapy can be withheld in mildly ill, ambulatory patients in whom viral infection is likely. Most guidelines suggest initial treatment with orally administered amoxicillin or amoxicillin/clavulanate or with intravenous cefuroxime when patients require hospitalization. In May, 2000, the Centers for Disease Control-convened Drug-Resistant S. pneumoniae Therapeutic Working Group identified oral beta-lactams including cefuroxime axetil, amoxicillin and amoxicillin/clavulanate as appropriate options for first line therapy of community-acquired pneumonia in ambulatory adults and children., Conclusions: New diagnostic techniques such as pneumococcal serologies and polymerase chain reaction testing have improved the ability to determine the microbiologic etiology of childhood pneumonia. Because these tests are not generally available, empiric treatment is necessary. Efforts to identify new intervention strategies, diagnostic tools, therapies and vaccines will be helpful in managing this disease.

The alarming increase of bacterial resistance has had a serious impact on treatment practices for patients with meningitis and has prompted investigation of other possibly effective antibiotic regimens with agents, such as gatifloxacin and trovafloxacin, that have excellent activity against Streptococcus pneumoniae. The use of fluoroquinolones in children has been limited by studies that report chondrotoxicity in young animals. Gatifloxacin, a new fluoroquinolone, was recently tested in a rabbit model of cephalosporin-resistant pneumococcal meningitis. In these studies, animals were infected with a ceftriaxone-resistant (minimal inhibitory concentration [MIC], 4 microg/mL; minimal bactericidal concentration [MBC], 4 microg/mL) and gatifloxacin-susceptible (MIC, 0.125 microg/mL; MBC, 0.25 microg/mL) strain of S. pneumoniae and were treated with either a single- or divided-dose regimen of gatifloxacin. Results from these studies are reviewed and compared with data from other studies that used a similar rabbit model of pneumococcal meningitis. Overall, it was found that the bacteriologic efficacy of gatifloxacin against S. pneumoniae was as effective as that of conventional regimens. Bactericidal activity of gatifloxacin was correlated with the area under the time-concentration curve-to-MBC ratio; maximal activity was achieved when gatifloxacin concentrations exceeded the MBC for the entire dosing interval.

Background: Lower respiratory tract infections are a common cause of morbidity among children. Among these infections pneumonia is the most serious illness and can be difficult to diagnose. The etiology of pneumonia is still partly unknown, primarily because of difficulty in obtaining adequate samples and lack of reliable diagnostic methods., Etiology of Pneumonia: Streptococcus pneumoniae is recognized as an important cause of pediatric pneumonia regardless of age in both the inpatient and outpatient setting. In developed countries S. pneumoniae probably accounts for 25 to 30% of cases of pediatric community-acquired pneumonia. Viruses (mostly respiratory syncytial virus) are responsible for approximately 20% of cases, and Chlamydia pneumoniae and Mycoplasma pneumoniae occur commonly in older children., Future Challenges: Despite the effectiveness of antimicrobial therapy, the emergence of resistant bacterial pathogens has resulted in increased interest in developing more effective vaccines. If conjugate pneumococcal vaccines prove effective at eradicating carriage of pneumococci in the nasopharynx, immunization may be an important tool against the spread of pneumococcal disease. Future challenges include implementation of effective intervention strategies, production of simple diagnostic tools and development of effective vaccines.

The UspA1 and UspA2 proteins of Moraxella catarrhalis are structurally related, are exposed on the bacterial cell surface, and migrate as very high-molecular-weight complexes in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Previous analysis of uspA1 and uspA2 mutants of M. catarrhalis strain 035E indicated that UspA1 was involved in adherence of this organism to Chang conjunctival epithelial cells in vitro and that expression of UspA2 was essential for resistance of this strain to killing by normal human serum (C. Aebi, E. R. Lafontaine, L. D. Cope, J. L. Latimer, S. R. Lumbley, G. H. McCracken, Jr., and E. J. Hansen, Infect. Immun. 66:3113-3119, 1998). In the present study, isogenic uspA1, uspA2, and uspA1 uspA2 mutations were constructed in three additional M. catarrhalis strains: 012E, TTA37, and 046E. The uspA1 mutant of strain 012E had a decreased ability to attach to Chang cells. However, inactivation of the uspA1 gene in both strain TTA37 and strain 046E did not cause a significant decrease in attachment ability. Inactivation of the uspA2 gene of strain TTA37 did result in a loss of attachment ability. Nucleotide sequence analysis revealed that the predicted protein encoded by the uspA2 genes of both strains TTA37 and 046E had a N-terminal half that resembled the N-terminal half of UspA1 proteins, whereas the C-terminal half of this protein was nearly identical to those of previously characterized UspA2 proteins. The gene encoding this "hybrid" protein was designated uspA2H. PCR-based analysis revealed that approximately 20% of M. catarrhalis strains apparently possess a uspA2H gene instead of a uspA2 gene. The M. catarrhalis uspA1, uspA2, and uspA2H genes were cloned and expressed in Haemophilus influenzae cells, which were used to prove that both the UspA1 and UspA2H proteins can function as adhesins in vitro.