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1.  Use of the Complete Blood Cell Count in Early-Onset Neonatal Sepsis 
Background
Early-onset sepsis is an important cause of morbidity and mortality in neonates, and its diagnosis remains challenging. The complete blood cell count and differential have been previously evaluated as diagnostic tools for early-onset sepsis in small, single-center reports. We evaluated the diagnostic accuracy of the complete blood count and differential in early-onset sepsis in a large, multicenter population of neonates admitted to the neonatal intensive care unit.
Methods
Using a cohort of 166,092 neonates with suspected early-onset sepsis with cultures admitted to 293 neonatal intensive care units, we calculated odds ratios and receiver operating characteristic curves for complete blood cell count indices and prediction of a positive culture. We determined sensitivity, specificity, and likelihood ratios for various commonly used cut-off values from the complete blood cell count.
Results
Low white blood cell counts, low absolute neutrophil counts, and high immature-to-total neutrophil ratios were associated with increasing odds of infection (highest odds ratios: 5.38, 6.84, and 7.97, respectively). Specificity and negative predictive values were high (73.7–99.9% and >99.8%). However, sensitivities were low (0.3–54.5%) for all complete blood cell count indices analyzed.
Conclusion
Low white blood cell count, absolute neutrophil count, and high immature-to-total neutrophil ratio were associated with increasing odds of infection, but no complete blood cell count-derived index possesses the sensitivity to rule out reliably early-onset sepsis in neonates.
doi:10.1097/INF.0b013e318256905c
PMCID: PMC3399972  PMID: 22531231
neonatal; early-onset sepsis; blood cell count
2.  Use of the Complete Blood Cell Count in Late-Onset Neonatal Sepsis 
Background
Late-onset sepsis is an important cause of morbidity and mortality in infants. Diagnosis of late-onset sepsis can be challenging. The complete blood cell count and differential have been previously evaluated as diagnostic tools for late-onset sepsis in small, single-center reports.
Objective
We evaluated the diagnostic accuracy of the complete blood count and differential in late-onset sepsis in a large multicenter population.
Study design
Using a cohort of all infants with cultures and complete blood cell count data from a large administrative database, we calculated odds ratios for infection, as well as sensitivity, specificity, positive and negative predictive values, and likelihood ratios for various commonly used cut-off values.
Results
High and low white blood cell counts, high absolute neutrophil counts, high immature-to-total neutrophil ratios, and low platelet counts were associated with late-onset sepsis. Associations were weaker with increasing postnatal age at the time of the culture. Specificity was highest for white blood cell counts <1000/mm3 and >50,000/mm3 (>99%). Positive likelihood ratios were highest for white blood cell counts <1000/mm3 (4.1) and platelet counts <50,000/mm3 (3.5).
Conclusion
No complete blood count index possessed adequate sensitivity to reliably rule out late-onset sepsis in this population.
doi:10.1097/INF.0b013e31825691e4
PMCID: PMC3399981  PMID: 22531232
neonatal; late-onset sepsis; blood cell count
3.  Antifungal Therapy and Outcomes in Infants with Invasive Candida Infections 
Background
Invasive candidiasis is a leading cause of mortality and morbidity in neonatal intensive care units. Treatment recommendations are limited by a lack of comparative outcomes data.
Methods
We identified all infants ≤120 days of age with positive blood, urine, or cerebrospinal fluid cultures for Candida sp. who received amphotericin B deoxycholate, fluconazole, amphotericin B lipid products, or combination therapy admitted to 1 of 192 neonatal intensive care units in the United States between 1997 and 2003. Primary outcome measures included overall mortality and therapeutic failure (combined outcome of duration of infection >7 days, need for additional antifungal therapy, or death prior to discharge). We compared outcomes by antifungal therapy using logistic regression, controlling for gestational age, day of life at start of antifungal therapy, delay in therapy, and site of infection.
Results
Overall, 138/730 (19%) infants died. On multivariable logistic regression, we observed higher overall mortality for infants receiving amphotericin B lipid products compared with infants receiving amphotericin B deoxycholate (OR 1.96 [95% CI: 1.16, 3.33]; p=0.01) or fluconazole (OR 2.39 [1.18, 4.83]; p=0.02).
Conclusions
Infants treated with amphotericin B lipid products had higher mortality than infants treated with either amphotericin B deoxycholate or fluconazole. This finding may be related to inadequate penetration of amphotericin B lipid products into the kidneys, inappropriate dosing in premature infants, or unknown differences in acuity of illness in infants treated with amphotericin B lipid products.
doi:10.1097/INF.0b013e3182467a72
PMCID: PMC3329577  PMID: 22189522
invasive candidiasis; infants; amphotericin B deoxycholate; fluconazole; amphotericin B lipid products
4.  Very Late Onset Infections in the Neonatal Intensive Care Unit 
Early Human Development  2011;88(4):217-225.
OBJECTIVE
We sought to determine the risk factors, incidence, and mortality of very late onset bacterial infection (blood, urine, or cerebrospinal fluid culture positive occurring after day of life 120) in preterm infants.
STUDY DESIGN
A retrospective observational cohort study of all very low birth weight infants cared for between day of life 120 and 365 in 292 neonatal intensive care units in the United States from 1997 to 2008.
RESULTS
We identified 3918 infants who were hospitalized beyond 120 days of life. Of these, 1027 (26%) were evaluated with at least 1 culture (blood, urine, or cerebrospinal fluid), and 276 (27%) of the evaluated infants had 414 episodes of culture-positive infection. Gram-positive organisms caused most of the infections (48%). The risk of death was higher in infants with positive cultures (odds ratio; 10.5, 95% confidence interval [7.2–15.5]) or negative cultures (4.8, [3.5–6.7]) compared to infants that were never evaluated with a culture (p<0.001). Mortality was highest with fungal infections (8/24, 33%) followed by Gram-positive cocci (40/142, 28%).
CONCLUSIONS
Important predictive risk factors for early and late onset sepsis (birth weight and gestational age) did not contribute to risk of developing very late onset infection. Evaluation for infection (whether positive or negative) was a significant risk factor for death. GPC and fungal infections were associated with high mortality.
doi:10.1016/j.earlhumdev.2011.08.009
PMCID: PMC3248995  PMID: 21924568
Neonate; VLBW; sepsis; late onset
5.  Early and Late Onset Sepsis in Late Preterm Infants 
Background
Preterm birth is increasing worldwide, and late preterm births, which comprise more than 70% of all preterm births, account for much of the increase. Early and late onset sepsis results in significant mortality in extremely preterm infants, but little is known about sepsis outcomes in late preterm infants.
Methods
This is an observational cohort study of infants < 121 days of age (119,130 infants less than or equal to 3 days of life and 106,142 infants between 4 and 120 days of life) with estimated gestational age at birth between 34 and 36 weeks, admitted to 248 neonatal intensive care units in the United States between 1996 and 2007.
Results
During the study period, the cumulative incidence of early and late onset sepsis was 4.42 and 6.30 episodes per 1000 admissions, respectively. Gram-positive organisms caused the majority of early and late onset sepsis episodes. Infants with early onset sepsis caused by Gram-negative rods and infants with late onset sepsis were more likely to die than their peers with sterile blood cultures (OR 4.39, 95% CI 1.71–11.23, P=0.002; and OR 3.37, 95% CI 2.35–4.84, P<0.001, respectively).
Conclusion
Late preterm infants demonstrate specific infection rates, pathogen distribution, and mortality associated with early and late onset sepsis. The results of this study are generalizable to late preterm infants admitted to the special care nursery or neonatal intensive care unit.
PMCID: PMC2798577  PMID: 19953725
blood culture; neonate; prematurity; infection; near term
6.  Group B Streptococcal Meningitis: Cerebrospinal Fluid Parameters in the Era of Intrapartum Antibiotic Prophylaxis 
Early human development  2009;85(10 Suppl):S5-S7.
Objective
Describe cerebrospinal fluid parameters in infants with culture-proven Group B streptococcal meningitis in the era of intrapartum antibiotic prophylaxis.
Study Design
Cohort study of the first lumbar puncture from 13,495 infants cared for at 150 neonatal intensive care units. We compared cerebrospinal fluid parameters [white blood cell count, red blood cell count, glucose, and protein], demographics, and outcomes between infants with and without Group B streptococcal meningitis.
Results
We identified 46 infants with Group B streptococcal meningitis. The median cerebrospinal fluid white blood cell count was 271 cells/mm3 for infants with Group B streptococcal meningitis and 6 cells/mm3 for infants without meningitis (p=0.0001). Of the infants with Group B streptococcal meningitis, 9/46 (20%) had negative blood cultures. Meningitis complicated 22/145 (15%) of episodes of early onset Group B streptococcal sepsis and 13/23 (57%) of episodes of late onset Group B streptococcal sepsis.
Conclusions
Group B streptococcal meningitis occurs in the presence of negative blood cultures. In hospitalized infants who undergo a lumbar puncture, Group B streptococcal sepsis is frequently complicated by GBS meningitis.
doi:10.1016/j.earlhumdev.2009.08.003
PMCID: PMC2783609  PMID: 19767158
Group B streptococcus; intrapartum antibiotic prophylaxis; meningitis
7.  Total Lymphocyte Count and World Health Organization Pediatric Clinical Stage as Markers to Assess Need to Initiate Antiretroviral Therapy among Human Immunodeficiency Virus-Infected Children in Moshi, Northern Tanzania 
Background
The World Health Organization (WHO) has recommended the use of clinical staging alone and with total lymphocyte count to identify HIV infected children in need of antiretroviral therapy (ART) in resource-limited settings, when CD4 cell count is not available.
Methods
We prospectively enrolled children obtaining care for HIV infection at the Kilimanjaro Christian Medical Centre Pediatric Infectious Diseases Clinic in Moshi, Tanzania between March 2004 and May 2006 for this cohort study.
Results
192 (89.7%) of 214 children met WHO ART initiation criteria based on clinical staging or CD4 cell count. Several low-cost measures identified individuals who met WHO ART initiation criteria to the following degree: WHO stages 3 or 4 had 87.5% (95% CI; 82.8 – 92.1) sensitivity and, by definition, 100% (CI; 100 – 100) specificity; WHO recommended advance disease TLC cutoffs: sensitivity = 23.9% (95% CI; 17.3 – 30.5) specificity = 78.2% (95% CI: 67.3 – 89.1). Low TLC was a common finding, (50/214; 23%); however, it did not improve the sensitivity or specificity of clinical staging in identifying the severely immunosuppressed stage 2 children. Growth failure or use of total lymphocyte counts in isolation were not reliable indicators of severe immunosuppression or need to initiate ART.
Conclusion
The use of total lymphocyte count does not improve the ability to identify children in need of ART compared to clinical staging alone. Low absolute lymphocyte count did not correlate with severe immunosuppression based on CD4 cell count in this cohort.
doi:10.1097/INF.0b013e3181950b7f
PMCID: PMC2724760  PMID: 19436238
HIV/AIDS; ART; TLC; pediatrics; immunosuppression; CD4
8.  Triazole use in the nursery: fluconazole, voriconazole, posaconazole, and ravuconazole 
Current drug metabolism  2013;14(2):193-202.
Invasive fungal infections in infants admitted to the neonatal intensive care unit are common and often fatal. The mainstay of therapy against invasive fungal infections is antifungal agents. Over the last two decades, the development and approval of these drugs evolved tremendously, and the azole class emerged as important agents in the treatment and prevention of invasive fungal infections. Among the azoles, fluconazole has been used extensively due to its favorable pharmacokinetics, excellent activity against Candida spp, and safety profile. This drug has been well studied in children but data for its use in infants are largely limited to Candida prophylaxis studies. Voriconazole, a second generation triazole, has excellent activity against Candida and Aspergillus spp. However, data on its use in neonates are extremely limited. Posaconazole and Ravuconazole are the newest agents of the triazole family. The antimicrobial spectrum of posaconazole is similar to voriconazole, but with additional activity against zygomycetes. Experience with posaconazole in children is very limited, and there are no reports of its use in infants. Ravuconazole is not approved for use by the FDA but studies in animals and humans show that it is often fungicidal and has favorable pharmacokinetics. In conclusion, the management of invasive fungal infections has progressed greatly over the last two decades with the azole antifungals playing a significant role. Related to this class, future research is needed in order to better assess dosing, safety, schedules and areas of use of these agents in infants admitted to the neonatal intensive care unit.
PMCID: PMC3541435  PMID: 22935068
antifungal agents; triazole; prematurity; infection; candida; aspergillosis
9.  Treatment and Prophylaxis of Invasive Candidiasis 
Seminars in perinatology  2012;36(6):416-423.
Invasive candidiasis (IC) is a leading cause of morbidity and mortality in preterm infants. Even if successfully treated, IC can cause significant neurodevelopmental impairment. Preterm infants are at increased risk for hematogenous Candida meningoencephalitis owing to increased permeability of the blood–brain barrier, so antifungal treatment should have adequate central nervous system penetration. Amphotericin B deoxycholate, lipid preparations of amphotericin B, fluconazole, and micafungin are first-line treatments of IC. Fluconazole prophylaxis reduces the incidence of IC in extremely premature infants, but its safety has not been established for this indication, and as yet, the product has not been shown to reduce mortality in neonates. Targeted prophylaxis may have a role in reducing the burden of disease in this vulnerable population.
doi:10.1053/j.semperi.2012.06.003
PMCID: PMC3582379  PMID: 23177800
invasive candidiasis; preterm infants; antifungals
10.  Urinary tract infection concordance with positive blood and cerebrospinal fluid cultures in the neonatal intensive care unit 
Objective
Urinary tract infections (UTI) are common in the neonatal intensive care unit (NICU). Blood, urine, and cerebrospinal fluid (CSF) cultures are frequently obtained to evaluate for infection. We sought to determine the concordance between positive urine cultures and blood or CSF cultures.
Study design
Infants <121 days of age with a UTI admitted to 322 NICUs managed by the Pediatrix Medical Group from 1997–2010 were identified. UTIs were defined by isolation of a single pathogenic organism in a urine sample obtained by catheterization or suprapubic tap. The UTI was concordant if the same organism was identified in the blood or CSF within 3 days of the urine culture.
Results
Of 5681 infants with a urine culture, 984 had 1162 UTIs. Nine hundred seventy-six UTIs (84%) had a blood culture collected within 3 days, and 127 (13%) were concordant. Of the 1162 UTIs, 77 (7%) had a CSF culture collected within 3 days, and 2 (3%) were concordant.
Conclusion
Collection of a urine culture in infants evaluated for late-onset sepsis is important. Concordance was observed in 13% of blood cultures and 3% of CSF cultures. These findings may be related to the initiation of empirical antimicrobial therapy before evaluation for disseminated infection or poor blood culture sensitivity.
doi:10.1038/jp.2012.111
PMCID: PMC3549035  PMID: 22935772
infant; sepsis
11.  Group B Streptococcus and Escherichia coli Infections in the Intensive Care Nursery in the Era of Intrapartum Antibiotic Prophylaxis 
Background
Group B Streptococcus (GBS) and Escherichia coli (E. coli) cause serious bacterial infections (SBIs) and are associated with morbidity and mortality in newborn infants. Intrapartum antibiotic prophylaxis (IAP) reduces early-onset SBIs caused by GBS. The effect of IAP on late-onset SBIs caused by these organisms is unknown.
Methods
We examined all blood, urine, and cerebrospinal fluid culture results from infants admitted from 1997–2010 to 322 neonatal intensive care units managed by the Pediatrix Medical Group. We identified infants with positive cultures for GBS or E. coli and compared the incidence of early- and late-onset SBI for each organism in the time period before (1997–2001) and after (2002–2010) universal IAP recommendations.
Results
We identified 716,407 infants with cultures, 2520 (0.4%) with cultures positive for GBS and 2476 (0.3%) with cultures positive for E. coli. The incidence of GBS early-onset SBI decreased between 1997–2001 and 2002–2010 from 3.5 to 2.6 per 1000 admissions, and the incidence for E. coli early-onset SBI remained stable (1.4 per 1000 admissions in both time periods). Over the same time period, the incidence of GBS late-onset SBI increased from 0.8 to 1.1 per 1000 admissions, and incidence of E. coli late-onset SBI increased from 2.2 to 2.5 per 1000 admissions.
Conclusions
In our cohort, the incidence of early-onset GBS SBI decreased, while the incidence of late-onset SBI for E. coli and GBS increased.
doi:10.1097/INF.0b013e318275058a
PMCID: PMC3572304  PMID: 23011013
infection; infant; sepsis; group B Streptococcus; Escherichia coli
12.  Risk Factors for Invasive Candidiasis in Infants >1500 g Birth Weight 
Background
We describe the incidence, risk factors, and outcomes of invasive candidiasis in infants >1500 g birth weight.
Methods
We conducted a retrospective cohort study of infants >1500 g birth weight discharged from 305 NICUs in the Pediatrix Medical Group from 2001–2010. Using multivariable logistic regression, we identified risk factors for invasive candidiasis.
Results
Invasive candidiasis occurred in 330/530,162 (0.06%) infants. These were documented from positive cultures from ≥1 of these sources: blood (n=323), cerebrospinal fluid (n=6), or urine from catheterization (n=19). Risk factors included day of life >7 (OR 25.2; 95% CI 14.6–43.3), vaginal birth (OR 1.6 [1.2–2.3]), exposure to broad-spectrum antibiotics (OR 1.6 [1.1–2.4]), central venous line (OR 1.8 [1.3–2.6]), and platelet count <50,000/mm3 (OR 3.7 [2.1–6.7]). All risk factors had poor sensitivities, low positive likelihood ratios, and low positive predictive values. The combination of broad-spectrum antibiotics and low platelet count had the highest positive likelihood ratio (46.2), but the sensitivity of this combination was only 4%. Infants with invasive candidiasis had increased mortality (OR 2.2 [1.3–3.6]).
Conclusions
Invasive candidiasis is uncommon in infants >1500 g birth weight. Infants at greatest risk are those exposed to broad-spectrum antibiotics and with platelet counts of <50,000/mm3.
doi:10.1097/INF.0b013e3182769603
PMCID: PMC3578110  PMID: 23042050
candidiasis; candidemia; neonates; neonatal intensive care unit
14.  Sports Medicine and Ethics 
Physicians working in the world of competitive sports face unique ethical challenges, many of which center around conflicts of interest. Team-employed physicians have obligations to act in the club’s best interest while caring for the individual athlete. As such, they must balance issues like protecting versus sharing health information, as well as issues regarding autonomous informed consent versus paternalistic decision-making in determining whether an athlete may compete safely. Moreover, the physician has to deal with an athlete’s decisions about performance enhancement and return to play, pursuit of which may not be in the athlete’s long-term best interests but may benefit the athlete and team in the short term. These difficult tasks are complicated by the lack of evidence-based standards in a field influenced by the lure of financial gains for multiple parties involved. In this article, we review ethical issues in sports medicine with specific attention paid to American professional football.
doi:10.1080/15265161.2013.828114
PMCID: PMC3899648  PMID: 24024796
sports medicine; ethics; conflict of interest; sports; football; athletes
15.  Neonatal fungal infections: when to treat? 
Early human development  2012;88(Suppl 2):S6-S10.
Candida infections are a major cause of morbidity and mortality in neonatal intensive care units. Mortality following Candida bloodstream infections is as high as 40%, and neurodevelopmental impairment is common among survivors. Because invasive fungal infections are common and extremely difficult to diagnose, empirical treatment with antifungal therapy should be considered in high-risk, low-birth-weight infants who fail to quickly respond to empirical antibacterial treatment. Risk factors to consider when deciding to administer empirical antifungal therapy include: prior exposure to third-generation cephalosporins, extreme prematurity, and presence of central venous catheters.
doi:10.1016/S0378-3782(12)70004-X
PMCID: PMC3512570  PMID: 22633516
neonatal intensive care unit; empirical; Candida; infection; antifungal therapy
16.  Effect of Sex and Race on Outcome in Patients Undergoing Congenital Heart Surgery: An Analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database 
The Annals of thoracic surgery  2012;94(6):10.1016/j.athoracsur.2012.05.124.
Background
Previous studies on the impact of race and sex on outcome in children undergoing cardiac operations were based on analyses of administrative claims data. This study uses clinical registry data to examine potential associations of sex and race with outcomes in congenital cardiac operations, including in-hospital mortality, postoperative length of stay (LOS), and complications.
Methods
The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS-CHSD) was queried for patients younger than 18 years undergoing cardiac operations from 2007 to 2009. Preoperative, operative, and outcome data were collected on 20,399 patients from 49 centers. In multivariable analysis, the association of race and sex with outcome was examined, adjusting for patient characteristics, operative risk (Society of Thoracic Surgeons–European Association for Cardiothoracic Surgery [STAT] mortality category), and operating center.
Results
Median age at operation was 0.4 years (inter-quartile range 0.1–3.4 years), and 54.4% of patients were boys. Race/ethnicity included 54.9% white, 17.1% black, 16.4% Hispanic, and 11.7% “other.” In adjusted analysis, black patients had significantly higher in-hospital mortality (odds ratio [OR], 1.67; 95% confidence interval [CI], 1.37–2.04; p < 0.001) and complication rate (OR, 1.15; 95% CI, 1.04–1.26; p < 0.01) in comparison with white patients. There was no significant difference in mortality or complications by sex. Girls had a shorter LOS than boys (−0.8 days; p < 0.001), whereas black (+2.4 days; p < 0.001) and Hispanic patients (0.9 days; p < 0.01) had longer a LOS compared with white patients.
Conclusions
These data suggest that black children have higher mortality, a longer LOS, and an increased complication rate. Girls had outcomes similar to those of boys but with a shorter LOS of almost a day. Further study of potential causes underlying these race and sex differences is warranted.
doi:10.1016/j.athoracsur.2012.05.124
PMCID: PMC3838919  PMID: 22884593
17.  Very low birth weight neonates who survive early-onset sepsis do not have an increased risk of developing late-onset sepsis 
Early human development  2012;88(11):905-909.
SUMMARY
Background
Very low birth weight neonates (≤1500 g, VLBWs) have a high rate of infection and distinct baseline immune function compared with more mature populations. In critically ill children and adults, sepsis increases subsequent infection risk. It is unknown whether sepsis modifies the risk of subsequent infection in VLBWs.
Methods
We conducted a retrospective cohort study of VLBWs ≤32 weeks gestation at birth cared for in 312 neonatal intensive care units in the United States from 1997–2011 (n=103,376). Early-onset sepsis (EOS, culture-positive only) and late-onset sepsis (LOS, culture-positive or clinical) cases were identified. Cox proportional hazards models were used to control for clinical variables between neonates with and without EOS to determine if EOS modified risk of LOS, necrotizing enterocolitis (NEC), or death.
Results
LOS occurred in 12,112/102,317 (11.8%) neonates without EOS and in 133/1059 (12.6%) of those with EOS. After adjustment for clinical variables, the risk of LOS was not different between neonates with or without a history of EOS (hazard ratio [HR]=0.92; 95% confidence interval [CI] 0.74, 1.16). EOS increased the risk of 120-day mortality (HR=1.78; 95% CI 1.49, 2.13).
Conclusions
In contrast to findings in children and adults, EOS was not associated with an increased risk of LOS in this cohort. Age-specific investigations are needed to determine if post-sepsis immunologic alterations are present.
doi:10.1016/j.earlhumdev.2012.07.009
PMCID: PMC3462255  PMID: 22840605
preterm; neonate; sepsis; immunoparalysis
18.  Pharmacokinetics and Safety of Fluconazole in Young Infants Supported with Extracorporeal Membrane Oxygenation 
Background
Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK), thus standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the PK of fluconazole in infants on ECMO.
Methods
Infants <120 days old received either intravenous fluconazole prophylaxis (25 mg/kg once a week) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected pre- and post-oxygenator around doses 1 and 2 to calculate PK indices and describe oxygenator extraction. A 1-compartment model was fit to the data using non-linear regression. Surrogate pharmacodynamic targets for efficacy were evaluated.
Results
Ten infants were enrolled. After dose 1 (n=9), the median clearance was 17 mL/kg/h, the median volume of distribution was 1.5 L/kg, and the median exposure in the first 24 hours (AUC0–24) was 322 h*mg/L. After multiple doses (n=7), the median clearance was 22 mL/kg/h, the median volume of distribution was 1.9 L/kg, and the AUC0–24 was 352 h*mg/L. After dose 1, 78% of infants achieved the prophylaxis target, while only 11% achieved the therapeutic target. Oxygenator extraction of fluconazole was minimal (−2.0%, standard deviation 15.0), and extraction was not correlated with age of the ECMO circuit (rho= − 0.05). There were no adverse events related to fluconazole.
Conclusions
Infants on ECMO had higher volume of distribution but similar clearance when compared with historical controls not on ECMO. In infants on ECMO, a fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections. However, higher doses may be needed for treatment.
doi:10.1097/INF.0b013e31825d3091
PMCID: PMC3444624  PMID: 22627870
fluconazole; Candida; extracorporeal membrane oxygenation; pharmacokinetics; infants
19.  Candida Virulence Properties and Adverse Clinical Outcomes in Neonatal Candidiasis 
The Journal of pediatrics  2012;161(3):441-447.e2.
Objective
To determine if premature infants with invasive Candida infection caused by strains with increased virulence properties have worse clinical outcomes than those infected with less virulent strains.
Study design
Clinical isolates were studied from 2 populations; premature infants colonized with Candida (commensal, n=27), and those with invasive candidiasis (n=81). Individual isolates of C. albicans and C. parapsilosis were tested for virulence in each of 3 assays: phenotypic switching, adhesion, and cytotoxicity. Invasive isolates were considered to have enhanced virulence if they measured more than 1 SD above the mean for the commensal isolates in at least 1 assay. Outcomes of patients with invasive isolates with enhanced virulence were compared with those with invasive isolates lacking enhanced virulence characteristics.
Results
61% of invasive isolates of C. albicans and 42% of invasive isolates of C. parapsilosis had enhanced virulence. All C. albicans cerebrospinal fluid (CSF) isolates (n=6) and 90% of urine isolates (n=10) had enhanced virulence, compared with 48% of blood isolates (n=40). Infants with more virulent isolates were younger at the time of positive culture and had higher serum creatinine.
Conclusions
Individual isolates of Candida species vary in their virulence properties. Strains with higher virulence are associated with certain clinical outcomes.
doi:10.1016/j.jpeds.2012.02.051
PMCID: PMC3419788  PMID: 22504098
C. albicans; C. parapsilosis; mortality; neurodevelopmental impairment; phenotypic switch; adhesion; cytotoxicity
20.  Pharmacokinetics and Tolerability of Single-Dose Daptomycin in Young Infants 
Background
Daptomycin is approved for the treatment of complicated skin and skin structure infections and Staphylococcus aureus bacteremia. We sought to characterize daptomycin single-dose pharmacokinetics and tolerability in young infants.
Methods
Subjects <120 days of age with suspected systemic infections were eligible for inclusion. Each subject was given a single 6 mg/kg intravenous dose of daptomycin. An average of 4 post-dose concentrations per infant was obtained.
Results
Data from 20 infants are presented. Median gestational age at birth and postnatal age were 32 weeks (range 23, 40) and 3 days (1, 85), respectively. The median area under the concentration curve at 24 hours, volume of distribution, total body clearance, and half-life of daptomycin were 262.4 mg*h/L (166.7, 340.2), 0.21 L/kg (0.11, 0.34), 0.021 L/hr/kg (0.016, 0.034), and 6.2 hours (3.7, 9.0), respectively. No adverse events related to daptomycin were observed, including changes in creatine phosphokinase concentrations.
Conclusions
Daptomycin clearance in young infants was similar to that in 2–6-year-olds and higher than that observed in adolescents and adults.
doi:10.1097/INF.0b013e31825d2fa2
PMCID: PMC3421038  PMID: 22627869
daptomycin; complicated skin and skin structure infections; Staphylococcus aureus; pharmacokinetics
22.  Emperic Antifungal Therapy and Outcomes in Extremely-Low-Birth-Weight Infants with Invasive Candidiasis 
The Journal of Pediatrics  2012;161(2):264-269.e2.
Objective
To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequent outcomes in premature infants.
Study design
This was a cohort study of infants ≤1000 g birth weight cared for at Neonatal Research Network sites. All infants had at least 1 positive culture for Candida. Emperic antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of emperic antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).
Results
136 infants developed invasive candidiasis. The incidence of death or NDI was lower for infants who received emperic antifungal therapy (19/38, 50%) compared with those who had not (55/86, 64%; odds ratio=0.27 [95% confidence interval 0.08–0.86]). There was no significant difference between the groups for any single outcome or other combined outcomes.
Conclusions
Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
doi:10.1016/j.jpeds.2012.01.053
PMCID: PMC3380169  PMID: 22424952
Candida; neonate; mortality; neurodevelopmental impairment
23.  Evidence-based guidelines for pediatric clinical trials: focus on StaR Child Health 
Clinical trials in children are challenging and filled with important ethical considerations that differ from adults. Given difficulties associated with pediatric clinical trials, off-label prescribing is a common practice in pediatrics, which can lead to adverse safety events and efficacy failures. To overcome these consequences, in the past 15 years, legislation in the USA and Europe has provided incentives to industry and increased government funding to conduct pediatric trials. Pediatric trial networks have also been formed to decrease the knowledge gap. However, challenges to performing pediatric trials and lack of standardization and guidelines regarding studies in children still exist. Standards for Research (StaR) in Child Health, begun in 2009, aims to improve the design, conduct and reporting of pediatric trials. This organization uses a consensus guideline approach involving academic, government and industry stakeholders to identify and disseminate best practices for pediatric trials. Six out of 11 planned standards are currently published.
doi:10.1586/ecp.12.52
PMCID: PMC3566240  PMID: 23121275
clinical trials; guidelines; pediatrics
24.  Risk Factors and Prevention of Late Onset Sepsis in Premature Infants 
Early human development  2010;86(Suppl 1):7-12.
Late-onset sepsis in premature infants is a major cause of morbidity, mortality, and increased medical costs. Risk factors include low birth weight, low gestational age, previous antimicrobial exposure, poor hand hygiene, and central venous catheters. Methods studied to prevent late-onset sepsis include early feedings, immune globulin administration, prophylactic antimicrobial administration, and improved hand hygiene. In this review, we will outline the risk factors for development of late-onset sepsis and evidence supporting methods for prevention of late-onset sepsis in premature infants.
doi:10.1016/j.earlhumdev.2010.01.012
PMCID: PMC2889164  PMID: 20116186
25.  Outcomes of Catheter-associated Infections in Pediatric Patients with Short Bowel Syndrome 
Children with short bowel syndrome requiring long-term total parenteral nutrition are at high risk for catheter-associated infections. The optimal management of catheter infections in this patient population is unknown. We conducted a retrospective observational study in children with short bowel syndrome to compare outcomes of catheter-associated infections treated with catheter removal plus antibiotic therapy versus antibiotic therapy alone.
doi:10.1097/MPG.0b013e3181b99d07
PMCID: PMC2847645  PMID: 20179637
short gut; children; line infection

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