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1.  Insulin Resistance and Glucose and Lipid Concentrations in a Cohort of Perinatally HIV-Infected Latin American Children 
We measured glucose, insulin, and lipids in 249 perinatally HIV-infected Latin American children. Only one subject had impaired fasting glucose; 6.8% had insulin resistance. Abnormalities in total, LDL and HDL cholesterol, and triglycerides were reported for 13%, 13%, 21%, and 34%, respectively. Continued follow up of this populationis necessary to characterize the evolution and clinical consequences of these findings.
PMCID: PMC3695016  PMID: 23360832
2.  Prevalence of Mycobacteremia among HIV-Infected Infants and Children in Northern Tanzania 
Mycobacterium tuberculosis is a common cause of bloodstream infections among HIV-infected adults in sub-Saharan Africa, and is associated with high morbidity and mortality. We found no cases of mycobacteremia among 93 ill, HIV-infected children in northern Tanzania, despite optimization of laboratory methods and selection of patients thought to be at highest risk for disseminated infection.
PMCID: PMC3696391  PMID: 23360831
mycobacteremia; children; Africa; Tanzania; tuberculosis
3.  Adverse Events Associated with Meropenem versus Imipenem/Cilastatin Therapy in a Large Retrospective Cohort of Hospitalized Infants 
Carbapenems are commonly used in hospitalized infants despite a lack of complete safety data and associations with seizures in older children. We compared the incidence of adverse events in hospitalized infants receiving meropenem versus imipenem/cilastatin.
We conducted a retrospective cohort study of 5566 infants treated with meropenem or imipenem/cilastatin in neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. Multivariable conditional logistic regression was performed to evaluate the association between carbapenem therapy and adverse events, controlling for infant factors and severity of illness.
Adverse events were more common with use of meropenem compared with imipenem/cilastatin (62.8/1000 infant days vs. 40.7/1000 infant days, P<0.001). There was no difference in seizures with meropenem vs. imipenem/cilastatin (adjusted odds ratio [OR] 0.96; 95% confidence interval 0.68, 1.32). The incidence of death, as well as the combined outcome of death or seizure, was lower with meropenem use—OR 0.68 (0.50, 0.88) and OR 0.77 (0.62, 0.95), respectively.
In this cohort of infants, meropenem was associated with more frequent but less severe adverse events when compared with imipenem/cilastatin.
PMCID: PMC3708263  PMID: 23838776
meropenem; imipenem/cilastatin; adverse events; infant
4.  Decline in Immature Transitional B Cells Following Hepatitis B Vaccination in Hepatitis B Positive Newborns 
Humoral immune responses are protective against HBV infection. We characterized B cell phenotypic changes in infants of HBsAg+ve mothers compared with normal and HBsAg−ve infants at birth and one year after HBV immunization. HBsAg+ve infants had higher immature transitional B-cells at birth, which normalized a year after immunization. Immature B-cell response to neonatal HBV exposure is associated with maternal-child transmission of HBV.
PMCID: PMC3708314  PMID: 23838779
Transitional B cells; HBV positive newborns; HBV vaccine
5.  Treating Acute Otitis Media in Young Children: What Constitutes Success? 
PMCID: PMC3710302  PMID: 23435311
acute otitis media; antimicrobial treatment; clinical trials; outcome measures
6.  Lipid Changes in Kenyan HIV-1-Infected Infants Initiating Highly Active Antiretroviral Therapy by One Year of Age 
Early highly active antiretroviral therapy (HAART) is recommended for HIV-1 infected infants. There are limited data on lipid changes during infant HAART.
Non-fasting total (TC), low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol, and triglycerides (TG) were measured at 0, 6 and 12 months. Correlates of lipid levels and changes post-HAART were assessed using linear regression.
Among 115 infants, pre-HAART median age was 3.8 months, CD4% was 19%, and weight-for-age z-score (WAZ) was −2.42. Pre-HAART median lipid levels were: TC, 108.7 mg/dl, LDL, 42.5 mg/dl, HDL, 29.4 mg/dl and TG, 186.9 mg/dl. Few infants had abnormally high TC (6.2%) or LDL (5.6%), but many had low HDL (76.5%) or high TG (69.6%). Higher pre-HAART WAZ and HAZ were each associated with higher pre-HAART TC (P=0.04 and P=0.01) and LDL (P=0.02 and P=0.008). From 0–6 months post-HAART, TC (P<0.0001), LDL (P<0.0001), and HDL (P<0.0001) increased significantly, and 23.1% (P=0.002), 14.0% (P=0.2), 31.3% (P<0.0001), and 50.8% (P=0.2) of infants had abnormally high TC, high LDL, low HDL, and high TG, respectively. Changes in TC and HDL were each associated with higher gain in WAZ (P=0.03 and P=0.01) and HAZ (P=0.01 and P=0.007). Increased change in LDL was associated with higher gain in HAZ (P=0.03). Infants on protease inhibitor (PI)-HAART had smaller HDL increase (P=0.004).
Infants had substantive increases in lipids, which correlated with growth. Increases in HDL were attenuated by PI-HAART. It is important to determine clinical implications of these changes.
PMCID: PMC3737429  PMID: 23385950
lipids; pediatric HIV-1; highly active antiretroviral therapy; infants; Africa
7.  Prevalence of Bacteremia in Hospitalized Pediatric Patients With Community-acquired Pneumonia 
National guidelines recommend obtaining blood cultures in children hospitalized with moderate or severe community-acquired pneumonia (CAP). The objectives of this study were to determine the prevalence of bacteremia in children, identify factors associated with bacteremia and quantify the influence of positive blood cultures on clinical management in children hospitalized with CAP.
This multicenter retrospective study included children from 60 days to 18 years of age requiring hospitalization for CAP. Categories analyzed were bacteremia, culture negative and no culture.
Blood cultures were performed in 369 (56%) of 658 children with CAP. The prevalence of bacteremia was 7% (4.7–10.1%) in patients with a blood culture obtained. Bacteremia occurred in 21% of patients with a pleural drainage procedure and 75% of patients with distant site of infection (eg, osteomyelitis). Patients with bacteremia had longer duration of fever before admission and higher C-reactive protein values compared with those with negative or no blood culture. However, differences in white blood cell count and erythrocyte sedimentation rate between those with bacteremia and those without were not significant. Contamination rates were low and similar across institutions, ranging from 1% to 3.8% (P = 0.63). Blood culture–directed changes in antibiotic management occurred in 33% of patients with a contaminated culture and 65% of bacteremic patients. Antibiotic therapy was narrowed in 26% of bacteremic patients at hospital discharge.
The prevalence of bacteremia was higher than previously reported in children hospitalized with CAP and consistent across children’s hospitals. Positive blood cultures should prompt change to narrow-spectrum antibiotic therapy.
PMCID: PMC3907948  PMID: 23518826
bacteremia; children; community-acquired pneumonia; hospitalized
8.  Safety of Perinatal Exposure to Antiretroviral Medications: Developmental Outcomes in Infants 
This study evaluated effects of perinatal exposure to antiretroviral (ARV) medications on neurodevelopment of HIV-exposed, uninfected infants.
HIV-exposed, uninfected infants (age 9-15 months) enrolled in SMARTT, a multisite prospective surveillance study, completed the Bayley Scales of Infant and Toddler Development—Third Edition (Bayley-III), assessing cognition, language, motor skills, social-emotional development, and adaptive behavior. Linear regression models were used to evaluate associations between Bayley-III outcomes in infants with and without perinatal and neonatal ARV exposure, by regimen (combination ARV [cARV] versus non-cARV), type of regimen (defined by drug class), and individual ARVs (for infants with cARV exposure), adjusting for maternal and infant health and demographic covariates.
As of May 2010, 374 infants had valid Bayley-III evaluations. Median age at testing was 12.7 months; 49% male, 79% black, 16% Hispanic. Seventy-nine percent were exposed to regimens containing protease inhibitors (PIs; 9% of PI-containing regimens also included non-nucleoside reverse transcriptase inhibitors [NNRTIs]), 5% to regimens containing NNRTIs (without PI), and 14% to regimens containing only nucleoside reverse transcriptase inhibitors (NRTIs). Overall, 83% were exposed to cARV. No Bayley-III outcome was significantly associated with overall exposure to cARV, ARV regimen, or neonatal prophylaxis. For individual ARVs, following sensitivity analyses, the adjusted group mean on the Language domain was within age expectations but significantly lower for infants with perinatal exposure to atazanavir (p=0.01).
These results support the safety of perinatal ARV use. Continued monitoring for adverse neurodevelopmental outcomes in older children is warranted, and the safety of atazanavir merits further study.
PMCID: PMC3723344  PMID: 23340561
HIV; ARV; infant; neurodevelopment; developmental assessment
9.  Resistance in Pediatric Patients Experiencing Virologic Failure with First- and Second-Line Antiretroviral Therapy 
The Pediatric infectious disease journal  2013;32(6):10.1097/INF.0b013e3182829092.
We examined HIV-1 resistance in children failing first-and second-line antiretroviral therapy (ART) in South Africa, all with clade C virus. Those exposed to full-dose ritonavir had multiple protease resistance mutations. Nineteen percent had wild type virus. Appropriate ART sequencing in sub-Saharan African children is essential for prolong treatment options.
PMCID: PMC3881960  PMID: 23303240
pediatric; antiretroviral therapy; genotype; resource-limited setting; virologic failure; resistance
10.  Adherence and Viral Suppression among Infants and Young Children Initiating Protease Inhibitor-Based Antiretroviral Therapy 
High levels of adherence to antiretroviral therapy (ART) are considered necessary to achieve viral suppression. We analyzed data from a cohort of HIV-infected children who were less than 2 years of age receiving protease inhibitor (PI)-based ART to investigate associations between viral suppression and adherence ascertained using different methods.
Data were from the pre-randomization phase of a clinical trial in South Africa of HIV-infected children initiating either ritonavir-boosted lopinavir (LPV/r)- or ritonavir-based ART. At scheduled visits during the first 24 weeks of enrollment, study pharmacists measured quantities of medications returned (MR) to the clinic. Caregivers answered questionnaires on missed doses and adherence barriers. Associations between adherence and viral suppression (HIV-1 RNA <400 copies/mL) were investigated by regimen.
By 24 weeks, 197/269 (73%) children achieved viral suppression. There was no association between viral suppression and caregiver reported missed doses or adherence barriers. For children receiving the LPV/r-based regimen, MR adherence to each of the three drugs in the regimen (LPV/r, lamivudine or stavudine) individually or together was associated with viral suppression at different adherence thresholds. For example, <85% adherence to any of the three medications significantly increased odds of lack of viral suppression (Odds Ratio [OR] 2.30 [95% CI: 1.30–4.07], p=.004). In contrast, for children receiving the ritonavir-based regimen, there was no consistent pattern of association between MR and viral suppression.
Caregiver reports of missed doses did not predict virologic response to treatment. Pharmacist medication reconciliation correlated strongly with virologic response for children taking a LPV/r-based regimen and appears to be a valid method for measuring pediatric adherence.
PMCID: PMC3624073  PMID: 23249913
adherence; pediatric ART; HIV; measurement
11.  Candida parapsilosis is a Significant Neonatal Pathogen: A Systematic Review and Meta-Analysis 
Candida is the third most common cause of late-onset neonatal sepsis in infants born at < 1500 g. C. parapsilosis infections are increasingly reported in preterm neonates in association with indwelling catheters.
We systematically reviewed neonatal literature and synthesized data pertaining to percentage of C. parapsilosis infections and mortality by meta-analyses. We also reviewed risk factors, virulence determinants, antimicrobial susceptibility patterns and outlined clinical management strategies.
C. parapsilosis infections comprised 33.47 % [95% CI, 30.02, 37.31] of all neonatal Candida infections. C. parapsilosis rates were similar in studies performed before the year 2000, 33.53 % [95% CI, 30.06, 37.40] (28 studies), to those after 2000, 27.00% [95% CI, 8.25, 88.37] (8 studies). The mortality due to neonatal Candida parapsilosis infections was 10.02% [95% CI, 7.66, 13.12]. Geographical variations in C. parapsilosis infections included a low incidence in Europe and higher incidence in North America and Australia. Biofilm formation was a significant virulence determinant and predominant risk factors for C. parapsilosis infections were prematurity, prior colonization and catheterization. Amphotericin B remains the antifungal drug of choice and combination therapy with caspofungin or other echinocandins may be considered in resistant cases.
C. parapsilosis is a significant neonatal pathogen, comprises a third of all Candida infections and is associated with 10% mortality. Availability of tools for genetic manipulation of this organism will identify virulence determinants and organism characteristics that may explain predilection for preterm neonates. Strategies to prevent horizontal transmission in the neonatal unit are paramount in decreasing infection rates.
PMCID: PMC3681839  PMID: 23340551
Neonate; Candida parapsilosis; systematic review; meta-analyses
12.  Isoniazid-Resistant Tuberculosis in Children: A Systematic Review 
Isoniazid resistance is an obstacle to the treatment of tuberculosis disease and latent tuberculosis infection in children. We aim to summarize the literature describing the risk of isoniazid-resistant tuberculosis among children with tuberculosis disease.
We did a systematic review of published reports of children with tuberculosis disease who had isolates tested for susceptibility to isoniazid. We searched PubMed, Embase and LILACS online databasesuptoJanuary 12, 2012.
Our search identified 3,403 citations, of which 95 studies met inclusion criteria. These studies evaluated 8,351 children with tuberculosis disease for resistance to isoniazid. The median proportion of children found to have isoniazid-resistant strains was 8%; the distribution was right-skewed (25th percentile: 0% and 75th percentile: 18%).
High proportions of isoniazid resistance among pediatric tuberculosis patients have been reported in many settings suggesting that diagnostics detecting only rifampin resistance are insufficient to guide appropriate treatment in this population. Many children are likely receiving sub-standard tuberculosis treatment with empirical isoniazid-based regimens, and treating latent tuberculosis infection with isoniazid may not be effective in large numbers of children. Work is needed urgently to identify effective regimens for the treatment of children sick with or exposed to isoniazid-resistant tuberculosis and to better understand the scope of this problem.
PMCID: PMC3709006  PMID: 23348808
drug resistance; mono-resistance; pediatric; INH; LTBI
13.  Hospital-based Surveillance for Rotavirus Gastroenteritis using Molecular Testing and Immunoassay during the 2011 Season in Botswana 
The Pediatric infectious disease journal  2013;32(5):10.1097/INF.0b013e3182847295.
We describe rotavirus testing results, demographics, seasonality and outcomes in children admitted with acute gastroenteritis to hospital during Botswana’s 2011 rotavirus season.
Rotavirus season extended from mid-June until the end of October with the rotavirus-specific case-fatality being 2.8%. Using PCR as the reference, the immunochromatographic test had a sensitivity of 76.5% and specificity of 68.0%. Rotavirus vaccine may significantly reduce childhood morbidity and mortality in Botswana.
PMCID: PMC3874800  PMID: 23340563
Rotavirus; Botswana; diarrhea; PCR; immunoassay
14.  Tenofovir Treatment Duration Predicts Proteinuria in a Multi-Ethnic United States Cohort of Children and Adolescents with Perinatal HIV-1 Infection 
Tenofovir is associated with renal proximal tubule injury. Such toxicity has not been extensively studied in HIV-1-infected children, in whom tenofovir is increasingly used.
History, urine and blood were collected at regular intervals from 448 children and adolescents with perinatal HIV-1 infection followed in the Pediatric HIV/AIDS Cohort study. Relationships between tenofovir use and proteinuria and chronic kidney disease (CKD) outcomes were examined using multivariable logistic regression models. Proteinuria was defined as at least one urine protein/creatinine ratio (uPCR) ≥0.2, and CKD as ≥2 sequential uPCR ≥0.2 or estimated glomerular filtration rates (eGFR) <60 mL/min/1.73 m2 with no subsequent resolution, or a clinical diagnosis not contradicted by a normal uPCR. Subjects with ≥2 uPCR <0.2, and no abnormal uPCR and eGFR comprised the comparison group.
Subjects were 47% male, 72% black, 24% Hispanic, with entry mean age (±standard deviation) of 11.5±2.5 years. Proteinuria prevalence at entry, and annually during 3 years, ranged from 10.3%–13.7%. The cumulative prevalence of proteinuria was 22% (94/434, 95% CI: 18%–26%) and CKD 4.5% (20/448, 95% CI: 2.7%–6.8%). Duration of tenofovir use was an independent predictor of proteinuria, with >3 years of exposure having the highest risk compared with no exposure (OR: 2.53, 95% CI: 1.23- 5.22, overall p=0.01). Overall, duration of tenofovir use did not significantly predict the presence of CKD.
Rates of proteinuria and CKD were lower than those seen in the pre-HAART era. However, prolonged exposure to tenofovir increases risk of renal injury.
PMCID: PMC3800277  PMID: 23249917
Tenofovir; proteinuria; chronic kidney disease; proximal tubules; nephrotoxicity; urine protein/creatinine ratio
15.  Cognitive Function and Neurodevelopmental Outcomes in HIV-Infected Children Older than 1 Year of Age Randomized to Early Versus Deferred Antiretroviral Therapy: The PREDICT Neurodevelopmental Study 
We previously reported similar AIDS-free survival at 3 years in children who were >1 year old initiating antiretroviral therapy (ART) and randomized to early vs. deferred ART in the PREDICT Study. We now report neurodevelopmental outcomes.
284 HIV-infected Thai and Cambodian children aged 1–12 years with CD4 counts between 15–24% and no AIDS-defining illness were randomized to initiate ART at enrollment (“early”, n=139) or when CD4 count became <15% or a CDC C event developed (“deferred”, n=145). All underwent age-appropriate neurodevelopment testing including Beery Visual Motor Integration (VMI), Purdue Pegboard, Color Trails and Child Behavioral Checklist (CBCL). Thai children (n=170) also completed Wechsler Intelligence Scale (IQ) and Stanford Binet Memory test. We compared week 144 measures by randomized group and to HIV-uninfected children (n=319).
At week 144, the median age was 9 years and 69 (48%) of the deferred arm children had initiated ART. The early arm had a higher CD4 (33% vs. 24%, p<0.001) and a greater percentage of children with viral suppression (91% vs. 40%, p<0.001). Neurodevelopmental scores did not differ by arm and there were no differences in changes between arms across repeated assessments in time-varying multivariate models. HIV-infected children performed worse than uninfected children on IQ, Beery VMI, Binet memory and CBCL
In HIV-infected children surviving beyond one year of age without ART, neurodevelopmental outcomes were similar with ART initiation at CD4 15–24% vs. < 15%; but both groups performed worse than HIV-uninfected children. The window of opportunity for a positive effect of ART initiation on neurodevelopment may remain in infancy.
PMCID: PMC3664246  PMID: 23263176
HIV; Children; ART; neurodevelopment; resource-limited settings
16.  Reducing the Frequency of Acute Otitis Media by Individualized Care 
We sought to determine if use of more stringent diagnostic criteria for acute otitis media (AOM) than currently advocated by the American Academy of Pediatrics (AAP), tympanocentesis and pathogen-specific antibiotic treatment (individualized care) would result in reducing the incidence of recurrent AOM and consequent tympanostomy tube surgery.
A 5 year longitudinal, prospective study in Rochester NY was conducted from July 2006 – July 2011 involving 254 individualized care children. When this individualized care group developed symptoms of AOM, strict diagnostic criteria were applied and a tympanocentesis was performed. Pathogen resistance to empiric high dose amoxicillin/clavulanate (80mg/kg of amoxicillin component) caused a change in antibiotic to an optimized choice. Legacy controls (n=208) were diagnosed with the same diagnostic criteria by the same physicians as the individualized care group and received the same empiric amoxicillin/clavulanate (80mg/kg of Amoxicillin component) but no tympanocentesis or change in antibiotic. Community control children (n=1020) were diagnosed according to current AAP guidelines and treated with high dose amoxicillin (80 mg/kg) without tympanocentesis as guideline recommended.
5.9% of children of the individualized care group compared to 14.4% of Legacy controls and 27.3% of community controls became otitis prone (OP), defined as 3 episodes of AOM within a 6-month time span or 4 AOM episodes within a 12-month time span (p<0.0001). 2.4% of the individualized care group compared to 6.3% of Legacy controls, and 14.8% of community controls received tympanostomy tubes (p<0.0001).
Individualized care of AOM significantly reduces the frequency of AOM and tympanostomy tube surgery. Use of strict diagnostic criteria for AOM and empiric antibiotic treatment using evidence-based knowledge of circulating otopathogens and their antimicrobial susceptibility profile also produces improved outcomes.
PMCID: PMC3681924  PMID: 23340550
otitis prone; acute otitis media; tympanostomy tubes; tympanocentesis; amoxicillin; amoxicillin/clavulanate
17.  Polymicrobial Acute Respiratory Infections in a Hospital-Based Pediatric Population 
The clinical impact of polymicrobial respiratory infections remains uncertain. Previous reports are contradictory regarding an association with severe disease.
Three hundred and forty-six specimens from children with acute respiratory illness identified at the University of Iowa Hospitals and Clinics Clinical Microbiology Laboratory (CML) were evaluated by DFA, and/or viral culture by CML and later by molecular study for the presence of influenza, parainfluenza (HPIV), respiratory syncytial virus (HRSV), adenovirus (HAdV), human metapneumovirus (HMPV), rhinovirus (HRV), and human bocavirus (HBoV). Demographic and clinical data were abstracted from medical records.
Multiple viruses were detected in 46 (21.7%) of 212 virus-positive specimens with the most frequent virus-virus combinations being HRV-HRSV (n=12), HRV-HBoV (n=6), and HRV-HPIV 3 (n=4). Risk factors for coinfection included: male gender (OR 1.70, 95% CI 0.83–3.46), 6 mos-1 yr age (OR 2.15, 95% CI 0.75–6.19), and history of immunosuppression (OR 2.05, 95% CI 0.99–4.23). Children with viral coinfections were less likely than children with single virus infections to be admitted to an intensive care unit (OR 0.32, 95% CI 1.12–9.17), however, this may be explained by undetected viral-bacterial coinfections.
HRV, HRSV, HBoV and polymicrobial infections were prevalent in this study. While the cross-sectional design could not easily examine polymicrobial infection and disease severity, prospective, population-based research regarding the clinical impact of such infections is warranted.
PMCID: PMC3701747  PMID: 23348811
acute respiratory infection; coinfection; epidemiology; polymicrobial infection
18.  Timing and Predictors of Fever and Infection after Craniotomy for Epilepsy in Children 
Fevers and leukocytosis after pediatric craniotomy trigger diagnostic evaluation and antimicrobial therapy for possible brain infection. This study determined the incidence and predictors of infection in infants and children undergoing epilepsy neurosurgery.
We reviewed the postoperative course of 100 consecutive surgeries for pediatric epilepsy, comparing those with and without infections for clinical variables and daily maximum temperatures, blood WBC and differential, and cerebrospinal fluid (CSF) studies.
Infections were the most common adverse events following these surgeries. Four patients (4%) had CSF infections and 12 had non-CSF infections (including one with distinct CSF and bloodstream infections). Most (88%) infections occurred before postoperative day 12 and were associated with larger resections involving ventriculostomies. Fevers (T ≥38.5°C) were observed in the first 12-days postsurgery in 43 % of cases, and were associated with patients undergoing hemispherectomy and multilobar resections. Fevers in the first three days postsurgery identified infections with 73% sensitivity, 69% specificity, and 70% accuracy; two (13%) patients with infections never developed fevers. Peripheral blood WBC >15,000 was found in 49% of patients and 5 cases of infections never had elevated WBC counts. WBC differential, CSF protein, RBC, WBC, and RBC/WBC ratios were poor predictors of infections. Longer hospital stays were associated with infections and hemispherectomy and multilobar resections. Patients with and without infections were equally likely to be seizure free after surgery.
Fevers and elevated blood WBC counts were common after pediatric epilepsy surgery, but CSF infections were uncommon. Positive cultures and other confirmatory microbiologic tests should drive changes in antimicrobial therapy after surgery.
PMCID: PMC3717398  PMID: 23348815
Seizure; neurosurgery; ventriculostomy; CSF; infection
19.  Biceps skin-fold thickness may detect and predict early lipoatrophy in HIV-infected pre-pubertal children on antiretroviral therapy 
The prevalence of lipoatrophy in children on antiretroviral therapy in Southern Africa is high, affecting around a third of children. Early diagnosis of lipoatrophy is essential for effective intervention to arrest progression.
Pre-pubertal children on antiretroviral therapy were recruited from a hospital-based family HIV clinic in Cape Town and followed up prospectively. Lipoatrophy was identified and graded by consensus between two HIV pediatricians. A dietician performed anthropometric measurements of trunk and limb fat. Anthropometric measurements in children with and without lipoatrophy were compared using multivariable linear regression adjusting for age and gender. The most discerning anthropometric indicators of lipoatrophy underwent Receiver Operating Characteristic curve analysis. The precision of anthropometric measurements performed by an inexperienced healthcare worker was compared to a research dietician.
36/100 recruits had lipoatrophy at baseline and a further 9 developed lipoatrophy by 15 month follow-up. Annual incidence of lipoatrophy was 12% (CI: 5–20%) per person-year of follow-up. A biceps skin-fold thickness <5mm at baseline had a sensitivity of 89% (CI: 67–100%) and a specificity of 60% (CI: 46–75%) for predicting which children would go on to develop lipoatrophy by 15 month follow-up. Negative and positive predictive values were 97% (CI: 91–100%) and 32% (CI: 14–50%).
Biceps skin-fold thickness <5mm in pre-pubertal children exposed to thymidine analogue-based antiretroviral therapy may be a useful screening tool to identify children who are likely to go on to develop lipoatrophy. The variation in precision of measurements performed by an inexperienced healthcare worker only marginally impacted performance.
PMCID: PMC4000309  PMID: 23249919
Lipoatrophy; Lipodystrophy; screening; biceps; skin-fold thickness; pre-pubertal; children; antiretroviral therapy; South Africa; HIV
21.  Role of Biofilm Formation in Ureaplasma Antibiotic Susceptibility and Development of Bronchopulmonary Dysplasia in Preterm Neonates 
Ureaplasma respiratory tract colonization is a risk factor for bronchopulmonary dysplasia (BPD) in preterm infants, but whether Ureaplasma isolates from colonized infants can form biofilms is unknown. We hypothesized that Ureaplasma isolates vary in capacity to form biofilms that contribute to their antibiotic resistance and ability to evade host immune responses. Study objectives were to 1) determine the ability of Ureaplasma isolates from preterm neonates to form biofilms in vitro; 2) compare the susceptibility of the sessile and planktonic organisms to azithromycin and erythromycin; and 3) determine the relationship of biofilm-forming capacity in Urea-plasma isolates and the risk for BPD.
Forty-three clinical isolates from preterm neonates and five ATCC strains were characterized for their capacity to form biofilms in vitro and antibiotic susceptibility was performed on each isolate pre- and post-biofilm formation.
Forty-one (95%) clinical and 4 of 5 (80%) ATCC isolates formed biofilms. All isolates were more susceptible to azithromycin (Minimum Inhibitory Concentration, MIC50 2 μg/mL) than erythromycin (MIC50 4 μg/mL), and biofilm formation did not significantly affect antibiotic susceptibility for the 2 tested antibiotics. The MIC50 and minimum biofilm inhibitory concentrations (MBIC50) for U. urealyticum clinical isolates for azithromycin were higher than for MIC50 and MBIC50 for U. parvum isolates. There were no differences in MIC or MBICs among isolates from BPD infants and non-BPD infants.
Capacity to form biofilms is common among Ureaplasma spp. isolates, but biofilm-formation did not impact MICs for azithromycin or erythromycin.
PMCID: PMC3600059  PMID: 23114371
Ureaplasma parvum; Ureaplasma urealyticum; bacterial biofilms; erythromycin; azithromycin; bronchopulmonary dysplasia
22.  Seasonality of Acute Otitis Media and the Role of Respiratory Viral Activity in Children 
Acute otitis media (AOM) occurs as a complication of viral upper respiratory tract infections in young children. AOM and respiratory viruses both display seasonal variation. Our objective was to examine the temporal association between circulating respiratory viruses and the occurrence of pediatric ambulatory care visits for AOM.
This retrospective study included 9 seasons of respiratory viral activity (2002-2010) in Utah. We used Intermountain Healthcare's electronic medical records to assess community respiratory viral activity via laboratory-based active surveillance and to identify children <18 years with outpatient visits and ICD-9 codes for AOM. We assessed the strength of the association between AOM and individual respiratory viruses using interrupted time series analyses.
During the study period, 96,418 respiratory viral tests were performed; 46,460 (48%) were positive. The most commonly identified viruses were: RSV (22%), rhinovirus (8%), influenza (8%), parainfluenza (4%), human metapneumovirus (3%), and adenovirus (3%). AOM was diagnosed during 271,268 ambulatory visits. There were significant associations between peak activity of RSV, human metapneumovirus, influenza A, and office visits for AOM. Adenovirus, parainfluenza, and rhinovirus were not associated with visits for AOM.
Seasonal RSV, human metapneumovirus, and influenza activity were temporally associated with increased diagnoses of AOM among children. These findings support the role of individual respiratory viruses in the development AOM. These data also underscore the potential for respiratory viral vaccines to reduce the burden of AOM.
PMCID: PMC3618601  PMID: 23249910
respiratory tract infection; influenza; RSV; human metapneumovirus; pediatrics
23.  Improved Vancomycin Dosing in Children Using Area-Under-the-Curve Exposure 
Our objectives were to: (1) determine the pharmacokinetic [PK] indices of vancomycin in pediatric patients; and (2) compare attainment of two target exposures: AUC/MIC ≥ 400 and trough concentration ≥ 15 mcg/mL.
The population-based PK modeling was performed using NONMEM 7.2 for children ≥ 3 months old who received vancomycin for ≥ 48 hr from 2003 to 2011. A one-compartment model with first-order kinetics was used to estimate clearance (CL), volume of distribution (Vd) and area-under-curve (AUC). Empiric Bayesian post-hoc individual parameters and Monte Carlo simulations (N=11,000) were performed.
Analysis included 702 patients with 1660 vancomycin serum concentrations. Median age was 6.6 (interquartile range [IQR] 2.2–13.4) yr, weight 22.7 (12.6–46) kg, and baseline serum creatinine (SCr) 0.40 (0.30–0.60) mg/dL. Final model PK indices were: CL(L/h) = 0.248*Wt0.75*(0.48/SCr)0.361*(ln(age)/7.8)0.995; and Vd(L) = 0.636*Wt. Using these parameters and the observed MIC distribution, Monte Carlo simulation indicated that the initial median dose of 44 (39–52) mg/kg/day was inadequate in most subjects. Regimens of 60 mg/kg/day for subjects ≥ 12 years old and 70 mg/kg/day for those < 12 years old achieved target AUC/MIC in ~ 75% and trough concentrations ≥ 15 in ~ 45% of virtual subjects. An AUC/MIC ~ 400 corresponded to trough concentration ~ 8 to 9 mcg/mL.
Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine, and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC ≥ 400 in 75% of patients.
PMCID: PMC3632448  PMID: 23340565
Vancomycin; children; pediatrics; antibiotic; Staphylococcus aureus; pharmacokinetic; pharmacodynamic
24.  Impact of Maternal and Infant Antiretroviral Drug Regimens on Drug Resistance in HIV-Infected Breastfeeding Infants 
The Pediatric infectious disease journal  2013;32(4):10.1097/INF.0b013e31827f44ee.
The HPTN 046 trial evaluated the efficacy of extended infant nevirapine (NVP) administration for prevention of HIV transmission through breastfeeding. Infants received daily NVP to 6 weeks of age. HIV-uninfected infants (the intent-to-treat group) received daily NVP or placebo up to 6 months of age. We analyzed emergence of NVP resistance in infants who acquired HIV-infection despite prophylaxis.
HIV genotyping was performed using the ViroSeq HIV Genotyping System. Medians and proportions were used to summarize data. Two-sided Fisher’s exact tests were used to evaluate associations between categorical variables.
NVP resistance was detected in 12 (92.3%) of 13 infants who were HIV-infected by 6 weeks and in seven (28%) of 25 infants who were HIV-uninfected at 6 weeks and HIV-infected at 6 months of age (6/8=75% in the NVP arm, 1/17=5.9% in the placebo arm, P=0.001). Among those 25 infants, 4 had mothers who initiated an antiretroviral (ARV) treatment regimen by 6 months postpartum. In all 4 cases, the treatment regimen included a non-nucleoside reverse transcriptase inhibitor (NVP or efavirenz). NVP resistance was detected in all four of those infants by 6 months of age (4/4=100%). In contrast, only three (14.2%) of the remaining 21 HIV-infected infants whose mothers did not initiate ARV treatment developed NVP resistance (P=0.003).
Extended NVP prophylaxis significantly increased the risk of NVP resistance in infants who acquired HIV infection after 6 weeks of age. Treatment of maternal HIV infection was also associated with emergence of NVP resistance in HIV-infected, breastfed infants.
PMCID: PMC3826537  PMID: 23249916
Nevirapine resistance; prevention of mother-to-child transmission; extended nevirapine; HIV
25.  New Patterns in the Otopathogens Causing Acute Otitis Media Six to Eight Years After Introduction of Pneumococcal Conjugate Vaccine 
To describe NP and AOM otopathogens during the time frame 2007-2009, six to eight years after the introduction of 7-valent pneumococcal conjugate (PCV7) in the US and to compare nasopharyngeal (NP) colonization and acute otitis media (AOM) microbiology in children 6 to 36 months of age having 1st and 2nd AOM episodes with children who are otitis prone.
Prospectively, the microbiology of NP colonization and AOM episodes was determined in 120 children with absent or infrequent AOM episodes. NP samples were collected at 7 routine visits between 6 and 30 months of age and at the time of AOM. For 1st and subsequent AOM episodes, middle ear fluid (MEF) was obtained by tympanocentesis. Eighty otitis prone children were comparatively studied. All 200 children received age-appropriate doses of PCV7.
We found PCV7 serotypes were virtually absent: (0.9% isolated from both NP and MEF) in both study groups. However, non-PCV7 serotypes replaced PCV serotypes such that the frequency of isolation of S. pneumoniae (Spn) was nearly equal to that of non-typeable Haemophilus influenzae (NTHi). M. catarrhalis (Mcat) was less common and Staphylococcus aureus infrequent in the NP and MEF from the two groups. The proportion of Spn, NTHi and Mcat causing AOM was similar in children with 1st and 2nd AOM episodes compared to otitis prone children. However, oxacillin-resistant Spn isolated from the NP and MEF was 19% for the absent/infrequent and 58% for the otitis prone groups, p<0.0001. Beta-lactamase producing NTHi occurred more frequently in the otitis prone group, p=0.04.
Six to 8 years after widespread use of PCV7, Spn strains expressing vaccine-type serotypes have virtually disappeared from the NP and MEF of vaccinated children. NP colonization and AOM has changed to non-PCV7 strains of Spn. NTHi continues to be a major AOM pathogen. The otopathogens in 1st and 2nd AOM and in otitis prone children are very similar although Spn and NTHi are more often antibiotic resistant in the otitis prone.
PMCID: PMC3959886  PMID: 19935445
Nasopharyngeal; AOM; S. pneumoniae; H. influenzae; M. catarrhalis

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