An integrated randomized intervention to reduce behavioral and psychosocial risks: pregnancy and neonatal outcomes.

While biomedical risks contribute to poor pregnancy and neonatal outcomes in African American (AA) populations, behavioral and psychosocial risks (BPSR) may also play a part. Among low income AA women with psychosocial risks, this report addresses the impacts on pregnancy and neonatal outcomes of an integrated education and counseling intervention to reduce BPSR, as well as the contributions of other psychosocial and biomedical risks. Subjects were low income AA women ≥18 years living in the Washington, DC, metropolitan area and seeking prenatal care. Subjects (n = 1,044) were screened for active smoking, environmental tobacco smoke exposure (ETSE), depression, or intimate partner violence (IPV) and then randomized to intervention (IG) or usual care (UCG) groups. Data were collected prenatally, at delivery, and postpartum by maternal report and medical record abstraction. Multiple imputation methodology was used to estimate missing variables. Rates of pregnancy outcomes (miscarriage, live birth, perinatal death), preterm labor, Caesarean section, sexually transmitted infection (STI) during pregnancy, preterm birth (<37 weeks), low birth weight (<2,500 g), very low birth weight (<1,500 g), small for gestational age, neonatal intensive care unit (NICU) admission, and >2 days of hospitalization were compared between IG and UCG. Logistic regression models were created to predict outcomes based on biomedical risk factors and the four psychosocial risks (smoking, ETSE, depression, and IPV) targeted by the intervention. Rates of adverse pregnancy and neonatal outcomes were high and did not differ significantly between IG and UCG. In adjusted analysis, STI during the current pregnancy was associated with IPV (OR = 1.41, 95% CI 1.04-1.91). Outcomes such as preterm labor, caesarian section in pregnancy and preterm birth, low birth weight, small for gestational age, NICU admissions and >2 day hospitalization of the infants were associated with biomedical risk factors including preexisting hypertension and diabetes, previous preterm birth (PTB), and late initiation of prenatal care, but they were not significantly associated with active smoking, ETSE, depression, or IPV. Neither the intervention to reduce BPSR nor the psychosocial factors significantly contributed to the pregnancy and neonatal outcomes. This study confirms that biomedical factors significantly contribute to adverse outcomes in low income AA women. Biomedical factors outweighed psychosocial factors in contributing to adverse pregnancy and neonatal outcomes in this high-risk population. Early identification and management of hypertension, diabetes and previous PTB in low income AA women may reduce health disparities in birth outcomes. Level of evidence I.

Variation in colonization, ADP-ribosylating and vacuolating cytotoxin, and pulmonary disease severity among mycoplasma pneumoniae strains.

RATIONALE: Mycoplasma pneumoniae was recently discovered to produce an ADP-ribosylating and vacuolating cytotoxin, designated CARDS toxin, which is hypothesized to be a primary pathogenic mechanism responsible for M. pneumoniae-induced pulmonary inflammation. It is unknown if cytotoxin production varies with M. pneumoniae strain or if variation in cytotoxin production affects pulmonary disease severity. OBJECTIVES: To examine the production of CARDS toxin by various strains of M. pneumoniae and compare the disease manifestations elicited by these strains in an experimental model of M. pneumoniae respiratory infection. METHODS: BALB/c mice were inoculated once intranasally with SP4 broth (negative control) or three different M. pneumoniae strains: M129-B7, M129-B9, or S1. Mice were assessed at 1, 2, 4, 7, 10, and 14 days after inoculation. Outcome variables included comparisons among M. pneumoniae strains relative to bronchoalveolar lavage (BAL) M. pneumoniae quantitative culture, CARDS toxin-based PCR, and CARDS toxin protein determinations, as well as cytokine and chemokine concentrations. Graded lung histopathologic score (HPS) was also assessed. MEASUREMENTS AND MAIN RESULTS: CARDS toxin concentrations were significantly increased in mice inoculated with strain S1 compared with mice inoculated with M129-B7 or M129-B9 strains. Quantitative M. pneumoniae culture and polymerase chain reaction were also significantly greater in mice infected with S1 strain compared with the other two strains, as were lung HPS and concentrations of IFN-γ, IL-12, IL-1α, macrophage inflammatory protein-1α, and keratinocyte-derived chemokine. In addition, a significant positive correlation was found between CARDS toxin concentration and lung HPS. CONCLUSIONS: CARDS toxin concentrations in BAL are directly linked to the ability of specific M. pneumoniae strains to colonize, replicate, and persist, and elicit lung histopathology. This variation among strains may predict the range in severity of pulmonary disease observed among patients.

Effectiveness of a combined home visiting and group intervention for low income African American mothers: the pride in parenting program.

Intervention strategies are needed to improve maternal and infant outcomes in minority populations living in poverty. Home visiting by nurses has improved outcomes for mothers and young children, but use of professional staff makes these programs expensive. Pride in Parenting was a randomized controlled trial of paraprofessional home visitation to provide health and developmental intervention for high-risk African American mothers in Washington, DC. This study proposed to test whether paraprofessional visitors drawn from the community could effectively influence health and mothers' parenting behaviors and attitudes. African American mothers with inadequate prenatal care were recruited at delivery and randomized to intervention or usual care groups. The intervention curriculum was delivered through both home visitation and parent-infant groups for 1 year. The intervention curriculum was designed to improve knowledge, influence attitudes, and promote life skills that would assist low-income mothers in offering better health oversight and development for their infants. Both intervention and usual care groups received monthly social work contact over the one-year study period to provide referrals for identified needs. The intervention participants improved their home environments, a characteristic important for promoting good child development. Mothers' perceptions of available social support improved and child-rearing attitudes associated with child maltreatment were reduced. Paraprofessional home visitors can be successful in improving the child-rearing environments and parenting attitudes for infants at risk, perhaps offering a less costly option to professional home visitors.

Efficacy of a randomized cell phone-based counseling intervention in postponing subsequent pregnancy among teen mothers.

Adolescent mothers in Washington, DC have a high rate of subsequent teen pregnancies, often within 24 months. Children of teen mothers are at risk for adverse psychosocial outcomes. When adolescents are strongly attached to parents, schools, and positive peers, they may be less likely to repeat a pregnancy. This study tested the efficacy of a counseling intervention delivered by cell phone and focused on postponing subsequent teen pregnancies by strengthening healthy relationships, reproductive practices, and positive youth assets. The objective of this study was to compare time to a repeat pregnancy between the intervention and usual care groups, and, secondarily, to determine whether treatment intensity influenced time to subsequent conception. Primiparous pregnant teens ages 15-19, were recruited in Washington, DC. Of 849 teens screened, 29.3% (n = 249) met inclusion criteria, consented to participate, and completed baseline measures. They were then randomized to the intervention (N = 124) or to usual care (N = 125). Intervention group teens received cell phones for 18 months of counseling sessions, and quarterly group sessions. Follow-up measures assessed subsequent pregnancy through 24 months post-delivery. A survival analysis compared time to subsequent conception in the two treatment groups. Additional models examined the effect of treatment intensity. By 24 months, 31% of the intervention and 36% of usual care group teens had a subsequent pregnancy. Group differences were not statistically significant in intent-to-treat analysis. Because there was variability in the degree of exposure of teens to the curriculum, a survival analysis accounting for treatment intensity was performed and a significant interaction with age was detected. Participants who were aged 15-17 years at delivery showed a significant reduction in subsequent pregnancy with increased levels of intervention exposure (P < 0.01), but not those ≥ 18 years. Adolescents ≥ 18 years faced considerable challenges to treatment success. Individual, social, and contextual factors are all important to consider in the prevention of repeat teen pregnancy. Cell phone-based approaches to counseling may not be the most ideal for addressing complex, socially-mediated behaviors such as this, except for selective subgroups. A lack of resources within the community for older teens may interfere with program success.

Reducing psychosocial and behavioral pregnancy risk factors: results of a randomized clinical trial among high-risk pregnant african american women.

OBJECTIVES: We evaluated the efficacy of a primary care intervention targeting pregnant African American women and focusing on psychosocial and behavioral risk factors for poor reproductive outcomes (cigarette smoking, secondhand smoke exposure, depression, and intimate partner violence). METHODS: Pregnant African American women (N = 1044) were randomized to an intervention or usual care group. Clinic-based, individually tailored counseling sessions were adapted from evidence-based interventions. Follow-up data were obtained for 850 women. Multiple imputation methodology was used to estimate missing data. Outcome measures were number of risks at baseline, first follow-up, and second follow-up and within-person changes in risk from baseline to the second follow-up. RESULTS: Number of risks did not differ between the intervention and usual care groups at baseline, the second trimester, or the third trimester. Women in the intervention group more frequently resolved some or all of their risks than did women in the usual care group (odds ratio = 1.61; 95% confidence interval = 1.08, 2.39; P = .021). CONCLUSIONS: In comparison with usual care, a clinic-based behavioral intervention significantly reduced psychosocial and behavioral pregnancy risk factors among high-risk African American women receiving prenatal care.

Effect of dexamethasone on respiratory syncytial virus-induced lung inflammation in children: results of a randomized, placebo controlled clinical trial.

Inflammatory mediators play a major role in the pathogenesis of respiratory syncytial virus (RSV) infection. The objective of this study was to evaluate the effect of i.v. dexamethasone on cytokine concentrations in tracheal aspirates (TA) of children with severe RSV disease and to correlate them with disease severity. Twenty-five cytokines were measured in TA obtained from children <2 yr old intubated for severe RSV disease, and enrolled in a double-blind study of i.v. dexamethasone (0.5 mg/kg; n = 22) vs. placebo (n = 19). Cytokine concentrations, measured at baseline and days 1 and 5 post-randomization using a multiplex assay, were compared within both treatment groups and correlated with: (i) tracheal white blood cell counts, (ii) tracheal RSV loads by culture and (iii) parameters of disease severity, including number of days of requirement for mechanical ventilation, intensive care unit (ICU), and hospitalization. At baseline interleukin (IL)-13 and IL-15 concentrations were significantly higher in the dexamethasone treatment group. On day 1 post-treatment, only MCP-1, eotaxin and IL-6 concentrations were significantly different but higher in the placebo group. On day 5: IL-13, IL-7, IL-8 and MIP-1alpha concentrations were higher in dexamethasone-treated patients. In both groups MIP-1beta inversely correlated with the days of ventilator support; MIP-1alpha, MIP-1beta and eotaxin inversely correlated with ICU days; and IL-6 inversely correlated with hospitalization regardless of the treatment assigned. Systemic administration of dexamethasone did not have a consistent effect on TA concentrations of pro-inflammatory cytokines. This may help explain, at least in part, the lack of clinical benefit of steroid treatment in children with severe RSV bronchiolitis.

The design, implementation and acceptability of an integrated intervention to address multiple behavioral and psychosocial risk factors among pregnant African American women.

BACKGROUND: African American women are at increased risk for poor pregnancy outcomes compared to other racial-ethnic groups. Single or multiple psychosocial and behavioral factors may contribute to this risk. Most interventions focus on singular risks. This paper describes the design, implementation, challenges faced, and acceptability of a behavioral counseling intervention for low income, pregnant African American women which integrated multiple targeted risks into a multi-component format. METHODS: Six academic institutions in Washington, DC collaborated in the development of a community-wide, primary care research study, DC-HOPE, to improve pregnancy outcomes. Cigarette smoking, environmental tobacco smoke exposure, depression and intimate partner violence were the four risks targeted because of their adverse impact on pregnancy. Evidence-based models for addressing each risk were adapted and integrated into a multiple risk behavior intervention format. Pregnant women attending six urban prenatal clinics were screened for eligibility and risks and randomized to intervention or usual care. The 10-session intervention was delivered in conjunction with prenatal and postpartum care visits. Descriptive statistics on risk factor distributions, intervention attendance and length (i.e., with < 4 sessions considered minimal adherence) for all enrolled women (n = 1,044), and perceptions of study participation from a sub-sample of those enrolled (n = 152) are reported. RESULTS: Forty-eight percent of women screened were eligible based on presence of targeted risks, 76% of those eligible were enrolled, and 79% of those enrolled were retained postpartum. Most women reported a single risk factor (61%); 39% had multiple risks. Eighty-four percent of intervention women attended at least one session (60% attended > or = 4 sessions) without disruption of clinic scheduling. Specific risk factor content was delivered as prescribed in 80% or more of the sessions; 78% of sessions were fully completed (where all required risk content was covered). Ninety-three percent of the subsample of intervention women had a positive view of their relationship with their counselor. Most intervention women found the session content helpful. Implementation challenges of addressing multiple risk behaviors are discussed. CONCLUSION: While implementation adjustments and flexibility are necessary, multiple risk behavioral interventions can be implemented in a prenatal care setting without significant disruption of services, and with a majority of referred African American women participating in and expressing satisfaction with treatment sessions.

Daptomycin therapy for invasive Gram-positive bacterial infections in children.

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.

Systemic cytokine profile in children with community-acquired pneumonia.

OBJECTIVES: Characterization of the systemic cytokine response in community-acquired pneumonia (CAP) may facilitate our understanding of the host immune response and provide a prognostic as well as diagnostic tool. Systemic cytokine characterization of CAP has been limited largely to a few integral cytokines in adults. METHODS: Analyses were performed to investigate whether significant relationships existed between an expanded serum cytokine profile and etiologies, manifestations, and outcomes of pediatric CAP. The serum concentrations of 15 cytokines were investigated in 55 hospitalized children with well-characterized CAP. RESULTS: Comparison of median cytokine concentrations among patients with CAP caused by Mycoplasma pneumoniae or Chlamydophila pneumoniae, Streptococcus pneumoniae, viruses, mixed infections, or unidentified pathogens revealed significant differences in IFN-alpha, IL-6, IL-17, GM-CSF, and TNF-alpha concentrations. The mixed infections category had significantly elevated concentrations of IFN-alpha, IL-6, GM-CSF, and TNF-alpha. There were significant correlations between concentrations of IL-6 and markers of disease severity (white blood cell band-forms, procalcitonin, and unequivocal consolidation). No single cytokine could reliably differentiate the etiologic cause of pneumonia. CONCLUSIONS: IL-6 is the only one of 15 serum cytokines studied that correlated with indicators of disease severity in childhood CAP. The applicability of cytokine profiles to identify microbiologic etiologies of pneumonia remains to be defined.

Treatment of experimental chronic pulmonary mycoplasmosis.

Mycoplasma pneumoniae infection has been associated with chronic lung disease. Treatment of chronic pulmonary mycoplasmosis has not been well investigated. BALB/c mice were intranasally inoculated once with M. pneumoniae or with sterile media (uninfected controls). Infected mice were treated with telithromycin or placebo daily for 10 days in the chronic phase of disease (18 months after inoculation). Mice (n=43) were evaluated before therapy and 1 day after completion of telithromycin. Treatment of infected mice with telithromycin at 18 months after infection significantly reduced chronic pulmonary histological inflammation compared with infected mice given placebo; however, this treatment did not improve airway obstruction or airway hyperresponsiveness. Therapy longer than 10 days may be necessary to improve pulmonary function.

Effects of large dosages of amoxicillin/clavulanate or azithromycin on nasopharyngeal carriage of Streptococcus pneumoniae, Haemophilus influenzae, nonpneumococcal alpha-hemolytic streptococci, and Staphylococcus aureus in children with acute otitis media.

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.

Epidemiology and evolution of invasive pneumococcal disease caused by multidrug resistant serotypes of 19A in the 8 years after implementation of pneumococcal conjugate vaccine immunization in Dallas, Texas.

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.

Prevalence of and risk factors for methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization in HIV-infected ambulatory patients.

BACKGROUND: Estimates of the prevalence of colonization with methicillin-resistant Staphylococcus aureus (MRSA) vary in HIV-infected patients. METHODS: HIV clinic patients were prospectively cultured. Bilateral nasal and axillary swabs were plated on BBL CHROMagar MRSA media. Molecular typing was done by pulse-field gel electrophoresis, and staphylococcal cassette chromosomemec typing was determined. A patient questionnaire was conducted to ascertain potential MRSA risk factors; medical records were reviewed. RESULTS: Fifteen of 146 (10.3%) patients had MRSA nasal colonization; 1 also had axillary colonization. Twelve of 15 isolates were staphylococcal cassette chromosomemec type IV, and 8 of 14 were USA300 or USA400 genotype. MRSA colonization was associated with lower CD4 cell count, not receiving current or recent antibiotics, history of prior MRSA or methicillin-susceptible Staphylococcus aureus infection (P < 0.05 for all), and a trend toward history of hospitalization or emergency department visit in the past year (P = 0.064). Current use of trimethoprim-sulfamethoxazole was protective for colonization: 0 of 29 trimethoprim-sulfamethoxazole recipients were colonized versus 15 of 117 nonrecipients, P = 0.04. In a multivariate logistic regression model, prior infection with either methicillin-susceptible S. aureus (odds ratio = 32.4, 95% confidence interval 3.04 to 345.42) or MRSA (odds ratio = 9.71, 95% confidence interval 2.20 to 43.01), not receiving current or recent antibiotics (odds ratio = 0.026, 95% confidence interval 0.002 to 0.412), and lower CD4 count (odds ratio 0.996, 95% confidence interval 0.992 to 0.999) were associated with MRSA colonization. DISCUSSION: The prevalence of MRSA nasal colonization was relatively high compared with prior studies; axillary colonization was rare. Prior staphylococcal infection (methicillin-susceptible S. aureus or MRSA), not receiving antibiotics, and lower CD4 count were associated with MRSA nasal colonization. Trimethoprim-sulfamethoxazole seemed to be protective of MRSA colonization.

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.

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.

Inducible clindamycin resistance and molecular epidemiologic trends of pediatric community-acquired methicillin-resistant Staphylococcus aureus in Dallas, Texas.

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 and immunologic evaluation of a single high dose of azithromycin for treatment of experimental Mycoplasma 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.

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.

Garenoxacin (BMS-284756) and moxifloxacin in experimental meningitis caused by vancomycin-tolerant pneumococci.

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.

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.