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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
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.  Old and new: Appropriate dosing for neonatal antifungal drugs in the nursery 
Early human development  2013;89(0 1):S25-S27.
Candida infections are a source of significant mortality and morbidity in the neonatal intensive care unit. Treatment strategies continue to change as additional antifungals become available and studies in neonates are performed. Amphotericin B deoxycholate has been favored for many years, but fluconazole has the most data supporting its use in neonatal Candida infections and is often employed for prophylaxis as well as treatment. Voriconazole and posaconazole have limited utility in the nursery and are rarely used. The echinocandins are increasingly administered for invasive Candida infections, although higher doses are required in neonates than in older children and adults.
doi:10.1016/S0378-3782(13)70009-4
PMCID: PMC3806495  PMID: 23809344
9.  Adverse Events Associated with Meropenem versus Imipenem/Cilastatin Therapy in a Large Retrospective Cohort of Hospitalized Infants 
Background
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.
Methods
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.
Results
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.
Conclusion
In this cohort of infants, meropenem was associated with more frequent but less severe adverse events when compared with imipenem/cilastatin.
doi:10.1097/INF.0b013e31828be70b
PMCID: PMC3708263  PMID: 23838776
meropenem; imipenem/cilastatin; adverse events; infant
10.  Sildenafil exposure and hemodynamic effect after stage II single-ventricle surgery 
Objective
To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery.
Design
Prospective, dose escalation trial.
Setting
Single-center, pediatric catheterization laboratory.
Patients
12 children post stage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range: 0.8, 4.0), weight 11 kg (8, 13), 9 females, and 10 with a single right ventricle.
Interventions
Catheterization and echocardiography performed before and immediately after single-dose intravenous sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 minutes).
Measurements
Peak sildenafil and des-methyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance.
Main Results
Maximum sildenafil concentrations ranged from 92–775 ng/ml and were above the in vitro threshold needed for 77% phosphodiesterase type-5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index (PVRI) in all 12 subjects (median PVRI 2.2 [range: 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU x m2; p<0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p=0.04) and saturations (+2% [0, 16], p=0.04) in those with baseline PVRI ≥2 WU x m2 (n=7). Change in saturations correlated inversely with change in PVRI (r2 = 0.74 p<0.01). Sildenafil also lowered mean blood pressure (−12% [−20, +10]; p=0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events.
Conclusions
Sildenafil demonstrated non-linear exposure with high inter-individual variability but was well tolerated and effectively lowered PVRI in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index.
doi:10.1097/PCC.0b013e31828aa5ee
PMCID: PMC3782306  PMID: 23823195
Single ventricle; sildenafil; bidirectional Glenn anastomosis; pulmonary hypertension; pulmonary vascular resistance; pharmacokinetics
11.  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
12.  10 × '20 Progress—Development of New Drugs Active Against Gram-Negative Bacilli: An Update From the Infectious Diseases Society of America 
Infections caused by antibiotic-resistant bacteria, especially the “ESKAPE” pathogens, continue to increase in frequency and cause significant morbidity and mortality. New antimicrobial agents are greatly needed to treat infections caused by gram-negative bacilli (GNB) resistant to currently available agents. The Infectious Diseases Society of America (IDSA) continues to propose legislative, regulatory, and funding solutions to this continuing crisis. The current report updates the status of development and approval of systemic antibiotics in the United States as of early 2013. Only 2 new antibiotics have been approved since IDSA's 2009 pipeline status report, and the number of new antibiotics annually approved for marketing in the United States continues to decline. We identified 7 drugs in clinical development for treatment of infections caused by resistant GNB. None of these agents was included in our 2009 list of antibacterial compounds in phase 2 or later development, but unfortunately none addresses the entire spectrum of clinically relevant GNB resistance. Our survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive. IDSA stresses our conviction that the antibiotic pipeline problem can be solved by the collaboration of global leaders to develop creative incentives that will stimulate new antibacterial research and development. Our aim is the creation of a sustainable global antibacterial drug research and development enterprise with the power in the short term to develop 10 new, safe, and efficacious systemically administered antibiotics by 2020 as called for in IDSA's “10 × '20 Initiative.”
doi:10.1093/cid/cit152
PMCID: PMC3707426  PMID: 23599308
antibacterial agents; antimicrobials; gram-negative bacilli; drug development; clinical trials; antibiotic pipeline
13.  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
14.  Early sepsis does not increase the risk of late sepsis in very low birth weight neonates 
The Journal of pediatrics  2013;162(5):942-948.e3.
Objective
To examine whether preterm very low birth weight (VLBW) infants have an increased risk of late-onset sepsis (LOS) following early-onset sepsis (EOS).
Study design
Retrospective analysis of VLBW infants (401-1500 g) born September 1998 through December 2009 who survived >72 hours and were cared for within the NICHD Neonatal Research Network. Sepsis was defined by growth of bacteria or fungi in a blood culture obtained ≤72 hr of birth (EOS) or >72 hr (LOS) and antimicrobial therapy for ≥5 days or death <5 d while receiving therapy. Regression models were used to assess risk of death or LOS by 120d and LOS by 120d among survivors to discharge or 120d, adjusting for gestational age and other covariates.
Results
Of 34,396 infants studied 504 (1.5%) had EOS. After adjustment, risk of death or LOS by 120d did not differ overall for infants with EOS compared with those without EOS [RR:0.99 (0.89-1.09)] but was reduced in infants born at <25wk gestation [RR:0.87 (0.76-0.99), p=0.048]. Among survivors, no difference in LOS risk was found overall for infants with versus without EOS [RR:0.88 (0.75-1.02)], but LOS risk was shorter in infants with BW 401-750 g who had EOS [RR:0.80 (0.64-0.99), p=0.047].
Conclusions
Risk of LOS after EOS was not increased in VLBW infants. Surprisingly, risk of LOS following EOS appeared to be reduced in the smallest, most premature infants, underscoring the need for age-specific analyses of immune function.
doi:10.1016/j.jpeds.2012.11.027
PMCID: PMC3622770  PMID: 23295144
Very low birth weight; early-onset sepsis; late-onset sepsis
15.  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
16.  Safety and Effectiveness of Meropenem in Infants With Suspected or Complicated Intra-abdominal Infections 
The safety and effectiveness of meropenem in young infants with suspected or confirmed intra-abdominal infections were evaluated. was well tolerated in this cohort of critically-ill infants, and the majority of infants treated with meropenem (84%) met the definition of therapeutic success.
Background. Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections.
Methods. Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score.
Results. Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%.
Conclusions. Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success.
Clinical Trials Registration. NCT00621192.
doi:10.1093/cid/cis758
PMCID: PMC3491861  PMID: 22955430
17.  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
18.  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
20.  Therapeutic Monitoring of Voriconazole in Children Less Than 3 Years of Age: A Case Report and Summary of Voriconazole Concentrations for 10 Children 
Voriconazole is the treatment of choice for invasive aspergillosis and its use is increasing in pediatrics. Minimal pharmacokinetic data exist in young children. We report voriconazole concentrations for 10 children less than <3 years of age and pharmacokinetic parameters for one infant who had therapeutic drug monitoring performed. Trough concentrations were unpredictable based on dose, highlighting the need to follow values during therapy.
doi:10.1097/INF.0b013e31824acc33
PMCID: PMC3356483  PMID: 22301479
invasive aspergillosis; pediatric; voriconazole; pharmacokinetic; therapeutic drug monitoring
21.  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
22.  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
23.  Outcomes Following Candiduria in Extremely Low Birth Weight Infants 
Extremely low birth weight (ELBW) infants with candiduria are at substantial risk for death or neurodevelopmental impairment. Therefore, identification of candiduria should prompt a systemic evaluation for disseminated Candida infection and initiation of treatment in all ELBW infants.
Background. Candidiasis carries a significant risk of death or neurodevelopmental impairment (NDI) in extremely low birth weight infants (ELBW; <1000 g). We sought to determine the impact of candiduria in ELBW preterm infants.
Methods. Our study was a secondary analysis of the Neonatal Research Network study Early Diagnosis of Nosocomial Candidiasis. Follow-up assessments included Bayley Scales of Infant Development examinations at 18–22 months of corrected age. Risk factors were compared between groups using exact tests and general linear modeling. Death, NDI, and death or NDI were compared using generalized linear mixed modeling.
Results. Of 1515 infants enrolled, 34 (2.2%) had candiduria only. Candida was isolated from blood only (69 of 1515 [4.6%]), cerebrospinal fluid (CSF) only (2 of 1515 [0.1%]), other sterile site only (not urine, blood, or CSF; 4 of 1515 [0.3%]), or multiple sources (28 of 1515 [2%]). Eleven infants had the same Candida species isolated in blood and urine within 3 days; 3 (27%) had a positive urine culture result first. Most urine isolates were Candida albicans (21 of 34 [62%]) or Candida parapsilosis (7 of 34 [29%]). Rate of death or NDI was greater among those with candiduria (50%) than among those with suspected but not proven infection (32%; odds ratio, 2.5 [95% confidence interval, 1.2–5.3]) after adjustment. No difference in death and death or NDI was noted between infants with candiduria and those with candidemia.
Conclusions. These findings provide compelling evidence that ELBW infants with candiduria are at substantial risk of death or NDI. Candiduria in ELBW preterm infants should prompt a systemic evaluation (blood, CSF, and abdominal ultrasound) for disseminated Candida infection and warrants treatment.
doi:10.1093/cid/cir800
PMCID: PMC3258271  PMID: 22144537
24.  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
25.  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

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