Evolution and Virulence of Serogroup 6 Pneumococci on a Global Scale

To study the evolution and virulence of pneumococcal populations, we used multilocus sequence typing to identify the major clones among 212 carriage and invasive isolates expressing capsular serogroup 6 from 39 countries. The global population consisted of 8 major complexes and 6 minor complexes of related clones and 32 clones of diverse origin. Surprisingly, serotype 6A clones evolved by mutation nearly as often as by recombination, whereas serotype 6B clones evolved almost exclusively by recombination (P = 0.0029). This is the first report of population genetic differences among serotypes of this species. The largest clonal complex was associated with invasive disease (P = 0.019) and included a common ancestor for five previously identified drug-resistant clones. The putative ancestors of the major clonal complexes were represented by a greater proportion of carriage isolates than were their descendents (P = 0.001), and the ancestors tended to be less virulent than their descendents in a mouse model of infection. These data suggested that virulent serogroup 6 clones have evolved multiple times from less-virulent ancestral clones

Use of Clindamycin Disks To Detect Macrolide Resistance Mediated by ermB and mefE in Streptococcus pneumoniae Isolates from Adults and Children

We studied 198 macrolide-resistant S. pneumoniae isolates obtained from adults and children to evaluate whether 2-μg clindamycin disks can distinguish between isolates manifesting ermB- versus mefE-mediated resistance to clarithromycin and to determine the relative frequency with which each resistance mechanism occurred in these populations. The mefE gene was predominant among 109 isolates from children, occurring in 73.4% versus 50.6% of 89 isolates from adults. Three isolates (1.5%) did not amplify either gene. Among 125 mefE(+) isolates, the MIC of clarithromycin at which 90% of the isolates tested were inhibited, determined by Etest, was 32 μg/ml versus >256 μg/ml in 70 ermB(+) isolates. All ermB(+) isolates were highly resistant to clindamycin (MICs >256 μg/ml), whereas all mefE(+) isolates were susceptible to clindamycin using the 2-μg disk. Testing S. pneumoniae from the respiratory tract for susceptibility to clindamycin by agar disk diffusion is an easy and inexpensive method to estimate the frequency of resistance mediated by ermB in specific patient populations. Macrolide resistance mediated by ermB is usually of greater magnitude than that due to mefE. Clinical studies are needed to determine the significance of high- versus low-level macrolide resistance in S. pneumoniae

Risk of tuberculosis among Alabama children and adolescents treated with tumor necrosis factor inhibitors: a retrospective study

Abstract Background Tumor Necrosis Factor inhibitors (TNFi) have dramatically improved the outlook for patients with inflammatory arthritides and bowel disease (IBD), but are associated with increased infection risks, including tuberculosis (TB). Pediatric inflammatory diseases are uncommon, and the risk of TB in children taking TNFi remains unclear. The objective of this study was to report the incidence of TB disease among TNFi recipients at a single pediatric medical center serving most of Alabama compared to that of the general population of Alabama children. Methods Instances of TNFi usage among patients under age 20 years from July 1, 2007 through April 17, 2015 were captured from electronic health records at Children’s of Alabama (CoA), which has the only pediatric rheumatology clinic in Alabama, and where a substantial number of children in Alabama with inflammatory bowel disease receive care., and reports of TB cases were obtained from the Alabama Department of Public Health (ADPH). Incidence was expressed as TB cases/10,000 person-years, using population estimates from the Alabama Center for Health Statistics. Results 1033 Alabama patients at CoA who were residents of Alabama were identified who received TNFi for a total of 1564 person-years. One adolescent on TNFi developed severe extrapulmonary TB (incidence density = 6.4 per 10,000; 95% CI 0.9–45.4 per 10,000). Sixty-three cases occurred in persons not on TNFi (incidence density = 0.064 per 10,000; 95% CI 0.050–0.082 per 10,000). Conclusions One case of TB disease among TNFi-exposed children was identified for 1564 person-years in Alabama residents. Although rare, this is higher than expected relative to the general rate of TB in Alabama. Thus, continued diagnostic vigilance for TB in children taking TNFi is required. Trial registration number Not applicable

Association of hypercholesterolemia incidence with antiretroviral treatment, including protease inhibitors, among perinatally HIV-infected children

Context: Antiretroviral therapy has been associated with hypercholesterolemia in HIV-infected children. Few longitudinal studies have been conducted to examine this association, however. Objective: To evaluate the incidence of and risk factors for development of hypercholesterolemia in a large pediatric study. Design: Prospective cohort study (Pediatric AIDS Clinical Trials Group 219C). Participants: A total of 2122 perinatally HIV-infected children free of hypercholesterolemia at entry. Outcome: Development of hypercholesterolemia (total cholesterol >= 220 mg/dL at 2 consecutive visits). Cox proportional hazards models were used to evaluate risk factors. Results: Thirteen percent of children had hypercholesterolemia at entry, and an additional 13% developed hypercholesterolemia during follow-up for an incidence rate of 3.4 cases per 100 person-years (95% confidence interval [CI]: 3.0 to 3.9). After adjustment for age, boosted protease inhibitor (PI) use (hazard ratio [HR] = 13.9, 95% CI: 6.73 to 28.6), nonboosted PI use (HR = 8.65, 95% CI: 4.19 to 17.9), and nonucleoside reverse transcriptase inhibitor use (FIR = 1.33, 95% CI: 1.04 to 1.71) were associated with increased risk of hypercholesterolemia, and higher viral load was protective (> 50,000 vs. :<= 400 copies/mL; HR = 0.59, 95% CI: 0.39 to 0.90). Self-reported adherent subjects had higher risk. Conclusions: PIs were significant risk factors for hypercholesterolemia. Higher viral load was protective and may reflect nonadherence. Further follow-up is critical to evaluate long-term consequences of chronic PI exposure and hypercholesterolemia

The Effects of CFTR and Mucoid Phenotype on Susceptibility and Innate Immune Responses in a Mouse Model of Pneumococcal Lung Disease.

Recent studies have reported the isolation of highly mucoid serotype 3 Streptococcus pneumoniae (Sp) from the respiratory tracts of children with cystic fibrosis (CF). Whether these highly mucoid Sp contribute to, or are associated with, respiratory failure among patients with CF remains unknown. Other mucoid bacteria, predominately Pseudomonas aeruginosa, are associated with CF respiratory decline. We used a mouse model of CF to study pneumococcal pneumonia with highly mucoid serotype 3 and non-mucoid serotype 19A Sp isolates. We investigated susceptibility to infection, survival, and bacterial counts from bronchoaviolar lavage samples and lung homogenates, as well as associated inflammatory cytokines at the site of infection, and lung pathology. Congenic CFTR-/- mice and wild-type (WT)-mice were infected intranasally with CHB756, CHB1126, and WU2 (highly mucoid capsular serotype 3, intermediately mucoid serotype 3, and less mucoid serotype 3, respectively), or CHB1058 (non-mucoid serotype 19A). BAL, lung homogenates, and blood were collected from mice 5 days post-infection. Higher CFU recovery and shorter survival were observed following infection of CFTR-/- mice with CHB756 compared to infection with CHB1126, WU2, or CHB1058 (P≤0.001). Additionally, CFTR-/- mice infected with CHB756 and CHB1126 were more susceptible to infection than WT-mice (P≤0.05). Between CFTR-/- mice and WT-mice, no significant differences in TNF-α, CXCL1/KC concentrations, or lung histopathology were observed. Our results indicate that highly mucoid type 3 Sp causes more severe lung disease than non-mucoid Sp, and does so more readily in the lungs of CFTR-/- than WT-mice

Genetic Relatedness of Levofloxacin-Nonsusceptible Streptococcus pneumoniae Isolates from North America

We characterized 32 levofloxacin-nonsusceptible Streptococcus pneumoniae (LNSP) isolates obtained from a broad geographic region of North America over a 5-year period by using capsular serotypes, antimicrobial susceptibility profiles, BOX-PCR, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). Sixteen international clones identified by the Pneumococcal Molecular Epidemiology Network also were included for comparison. Fifteen serotypes were represented, with serogroups 6, 9, 14, 19, and 23 accounting for 63% of isolates. Among isolates whose quinolone resistance-determining regions were sequenced, all contained gyrA and parC point mutations. Sixty-three percent were penicillin susceptible, and 84% were erythromycin susceptible. BOX-PCR analysis identified 39 different band patterns among 32 LNSP and 16 international clones and grouped 16 isolates, including 2 international clones, into seven unrelated groups of 2 to 4 isolates each. PFGE analysis identified 35 different band patterns among 32 LNSP and 16 international clones and grouped 21 isolates, including 3 international clones, into eight unrelated groups of 2 to 6 isolates each. MLST performed on 10 isolates identified five allelic profiles and separated 9 isolates into four groups of 2 to 3 isolates each. Overall, each typing method indicated that the LNSP were heterogeneous and that resistance to fluoroquinolones was not closely associated with a particular serotype or with coresistance to other antimicrobial classes and suggests that LNSP have likely arisen through independent mutational events as a result of selective pressure. However, seven LNSP were found to be related to three international clones by PFGE

In utero and postnatal exposure to antiretrovirals among hiv-exposed but uninfected children in the United States

OBJECTIVE Antiretroviral (ARV) drugs are routinely provided to HIV-infected pregnant women to prevent HIV mother-to-child transmission. Although ARV use has significantly reduced mother-to-child transmission to <2% in the United States, it remains crucial to monitor uninfected infants and children for adverse consequences of in utero ARV exposure. METHODS We studied neurodevelopmental function in HIV-exposed uninfected children who were enrolled in Pediatric AIDS Clinical Trials Group 219/219C, a multisite, prospective, cohort study. Mental and motor functioning were assessed with the Bayley Scales of Infant Development (BSID), first and second editions. ARV exposure information was collected during pregnancy or within the first years of life. Linear regression methods were used to evaluate the association of in utero ARV exposure on Mental Developmental Index and Psychomotor Developmental Index at 2 years of age, controlling for demographic factors (age, gender, and race/ethnicity) and potential confounders: test version, primary language, primary caregiver, caregiver education level, low birth weight, geographic and urban/rural location, birth year, and maternal illicit drug use. RESULTS Among 1840 infants who were born between 1993 and 2006, 1694 (92%) were exposed to ARV in utero and 146 (8%) were not exposed. After controlling for confounders, children who were exposed in utero to any ARV did not have lower Mental Developmental Index and Psychomotor Developmental Index scores than unexposed children. Among low birth weight infants, significantly higher BSID scores were observed for prenatally ARV-exposed than unexposed children. Maternal illicit drug use was reported for 17% of mothers but was not associated with BSID scores. CONCLUSIONS Mental and motor functioning scores were not lower for infants with in utero ARV exposure compared with no exposure. Although these results are reassuring, continued evaluation of uninfected children with in utero ARV exposure for long-term adverse outcomes is important

HIV Status and Other Risk Factors for Prevalent and Incident Sexually Transmitted Infection during Pregnancy (2000-2014)

Background. Sexually transmitted infections (STIs) are associated with adverse birth outcomes. Current prenatal STI screening guidelines define “risk” without explicit consideration of HIV status. Our objective was to test the hypothesis that HIV status is associated with bacterial STI in pregnant women. Methods. We designed a retrospective cohort study to identify pregnant women with HIV who delivered at our facility during 2000-2014. HIV+ women were compared to HIV- women with matching by year of delivery. Logistic regression was used to model adjusted odds of prevalent and incident STI. Prevalent STI was defined as chlamydia (CT), gonorrhea (GC), syphilis, or trichomoniasis detected on an initial prenatal screening test and incident STI as a newly positive result following a negative prenatal test. Results. The cohort included 432 women, 210 HIV+ and 222 HIV-. Most pregnant women were screened for STI (92% of HIV+ women and 74% of HIV- women). STI rates were high and particularly elevated in HIV+ women: 29% vs 18% (p=0.02), for prevalent STI and 11% vs 2% (p<0.001) for incident STI. Risk factors for prevalent STI were as follows: HIV status (aOR 3.0, CI: 1.4-6.4), Black race (aOR 2.7, 95% CI: 1.1-6.6), and more recent delivery (2007-2014 compared to 2000-2006) (aOR 2.3, CI: 1.1-4.7). HIV status was an independent risk factor for incident STI (aOR 7.2, CI: 2.1-25.0). Conclusion. Pregnant women who delivered in our center had high STI rates. Since HIV infection was independently associated with prevalent and incident STI, prenatal screening guidelines may need to incorporate HIV status as a high-risk group for repeat testing

<i>Sp</i> Strains used for Mouse Infections: Capsule Quantification Relative to WU2.

<p>‡Percentages were normalized to WU2</p><p>*Because Stains-All does not give the same intensity of staining capsules of different structures, a direct comparison by Stains-All of 19A with type 3 capsule was not made.</p><p><i>Sp</i> Strains used for Mouse Infections: Capsule Quantification Relative to WU2.</p

Comparison of CFU recovered from BAL and Lung Homogenates from CFTR^–/– and WT-mice infected with serotype 3 and 19A isolates of <i>SP</i> from CF patients.

<p>‡ = Mouse was significantly more susceptible to strain</p><p>ns = non-significant</p><p>Differences between CHB756, WU2, and CHB1058 were analyzed by 1-way ANOVA with the Tukey’s Multiple Comparison Post-Test.</p><p>Comparison of CFU recovered from BAL and Lung Homogenates from CFTR^–/– and WT-mice infected with serotype 3 and 19A isolates of <i>SP</i> from CF patients.</p