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1.  Postnatal Cytomegalovirus Infection and the Risk of Bronchopulmonary Dysplasia 
JAMA pediatrics  2015;169(12):e153785.
Importance
Postnatally acquired cytomegalovirus (CMV) is typically benign in term infants but, in very low birth weight (VLBW) infants, can cause pneumonitis and sepsis-like illness. Whether postnatal CMV infection results in long-term pulmonary sequelae in these infants is unknown.
Objective
To investigate the relationship between postnatal CMV infection and bronchopulmonary dysplasia (BPD) and mortality in a large, multicenter cohort of VLBW infants.
Design
Propensity-matched retrospective cohort study.
Setting
348 neonatal intensive care units in the United States from 1997–2012.
Participants
Hospitalized VLBW (<1500 g) infants.
Exposures
Postnatal CMV infection was defined as a diagnosis of CMV or detection of CMV from blood, urine, cerebrospinal fluid, or respiratory secretions on or after day of life 21. Infants with a CMV diagnosis or virologic detection of CMV prior to day of life 21 were not considered to have postnatal infection.
Main Outcomes and Measures
We matched infants with postnatal CMV infection 1:1 to comparison infants using propensity scores, and used Poisson regression to examine the effect of postnatal CMV on the combined risk of death or BPD at 36 weeks postmenstrual age. To describe features of postnatal CMV infection, we extracted clinical and laboratory data from 7 days before until 7 days after infants met criteria for postnatal CMV.
Results
Of 101,111 infants, 328 (0.3%) had postnatal CMV infection. We matched a comparison infant to 303 (92%) CMV-infected infants for a final cohort of 606 infants. The median gestational age and birth weight of this cohort were 25 weeks and 730 g, respectively. Postnatal CMV infection was associated with an increased risk of death or BPD at 36 weeks postmenstrual age (risk ratio [RR]: 1.21, 95% confidence interval [CI]: 1.10–1.32) and BPD (RR: 1.33, 95% CI: 1.19–1.50). Changes in cardiorespiratory status associated with postnatal CMV infection included a new requirement for vasopressor medications (9%), intubation for mechanical ventilation (15%), a new oxygen requirement (28%), and death (1.2%).
Conclusions and Relevance
In VLBW infants, postnatal CMV infection was associated with increased risk of BPD. Further studies are needed to determine the role of preventative measures against CMV in this population.
doi:10.1001/jamapediatrics.2015.3785
PMCID: PMC4699399  PMID: 26642118
cytomegalovirus; bronchopulmonary dysplasia; postnatal CMV infection
2.  Burden of Invasive Staphylococcus aureus Infections in Hospitalized Infants 
JAMA pediatrics  2015;169(12):1105-1111.
Importance
Staphylococcus aureus is a frequent cause of infection in hospitalized infants. These infections are associated with increased mortality and morbidity, and longer hospital stays, but data on the burden of S. aureus disease in hospitalized infants are limited.
Objective
To compare demographics and mortality of infants with invasive methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA), determine the annual proportion of S. aureus infections that were MRSA, and compare the risk of death following an invasive MRSA infection to the risk following an invasive MSSA infection.
Design
Multicenter retrospective study of a large, nationally representative cohort.
Setting
348 neonatal intensive care units managed by the Pediatrix Medical Group.
Participants
3888 infants with an invasive S. aureus infection who were discharged between 1997 and 2012.
Exposure
Invasive S. aureus infection.
Main Outcomes and Measures
Incidence of invasive S. aureus infections. Infant characteristics and mortality following MRSA or MSSA infection.
Results
The 3888 infants had 3978 invasive S. aureus infections (2868 MSSA, 1110 MRSA). The incidence of invasive S. aureus infection was 44.8 infections/10,000 infants. The yearly proportion of invasive infections caused by MRSA increased from 1997 to 2006 and has remained relatively stable since then. Infants with invasive MRSA or MSSA infections had similar gestational ages and birth weights. Invasive MRSA infections occurred more often at a younger postnatal age. For infants with available mortality data, more infants with invasive MSSA infections died at hospital discharge (N=237) than those with invasive MRSA infections (N=110). The proportion of infants who died following invasive MSSA or MRSA infection were similar: 237/2474 (9.6%) and 110/926 (11.9%), P=.05, respectively. Adjusted risk of death at hospital discharge was similar after invasive MSSA and MRSA infections overall (risk ratio, 1.19; 95% CI, 0.96-1.49). Risks of death at 7 and 30 days after invasive infection were similar between infants with invasive MSSA and MRSA infection.
Conclusion
Infant mortality following invasive MRSA and MSSA infections is similar. MSSA causes more infections and more deaths in infants than MRSA. Measures to prevent S. aureus infection should include MSSA in addition to MRSA.
doi:10.1001/jamapediatrics.2015.2380
PMCID: PMC4694042  PMID: 26502073
3.  Anaerobic Antimicrobial Therapy After Necrotizing Enterocolitis in VLBW Infants 
Pediatrics  2015;135(1):e117-e125.
OBJECTIVE:
To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (≤1500 g) infants.
METHODS:
We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobic antimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infants exposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity score stratified by NEC severity (medical and surgical). The primary composite outcome was in-hospital death or intestinal stricture. We assessed the relationship between anaerobic antimicrobial therapy and outcome by using a conditional logistic regression on the matched cohort.
RESULTS:
A total of 1390 infants exposed to anaerobic antimicrobial therapy were matched with 1390 infants not exposed. Mean gestational age and birth weight were 27 weeks and 946 g, respectively, and were similar in both groups. We found no significant difference in the combined outcome of death or strictures, but strictures as a single outcome were more common in the anaerobic antimicrobial therapy group (odds ratio 1.73; 95% confidence interval, 1.11–2.72). Among infants with surgical NEC, mortality was less common with anaerobic antimicrobial therapy (odds ratio 0.71; 95% confidence interval, 0.52–0.95).
CONCLUSIONS:
Anaerobic antimicrobial therapy was not associated with the composite outcome of death or strictures but was associated with an increase in intestinal strictures. This higher incidence of intestinal strictures may be explained by the fact that death is a competing outcome for intestinal strictures, and mortality was slightly lower in the anaerobic cohort. Infants with surgical NEC who received anaerobic antimicrobial therapy had lower mortality.
doi:10.1542/peds.2014-2141
PMCID: PMC4279070  PMID: 25511117
necrotizing enterocolitis; very low birth weight infants; anaerobes; antibiotics; mortality; intestinal strictures
4.  Late-Onset Bloodstream Infections in Hospitalized Term Infants 
Background
The epidemiology and incidence of late-onset bloodstream infections (BSIs) in premature infants has been described, but studies describing late-onset BSI in term infants are sparse. We sought to describe the pathogens, incidence, risk factors, and mortality of late-onset BSI in hospitalized term infants.
Methods
A cohort study was conducted of infants ≥37 weeks gestational age and ≤120 days old discharged from Pediatrix Medical Group neonatal intensive care units from 1997–2010. We examined all cultures obtained from day of life (DOL) 4–120 and used multivariable regression to assess risk factors for late-onset BSI.
Results
We found a total of 206,019 infants cared for between DOL 4 and 120, and the incidence of late-onset BSI was 2.7/1000 admissions. We identified Gram-positive organisms in 64% of the cultures and Gram-negative organisms in 26%. We found a decreased risk of late-onset BSI in infants with the following characteristics: small for gestational age, delivery by Cesarean section, antenatal antibiotic use, and discharged in the later years of the study. Late-onset BSI increased the risk of death after controlling for confounders (odds ratio 8.43 [95% confidence interval 4.42, 16.07]).
Conclusion
Our data highlight the importance of late-onset BSI in hospitalized term infants. We identified Gram-positive organisms as the most common pathogen, and late-onset BSI was an independent risk factor for death.
doi:10.1097/INF.0000000000000322
PMCID: PMC4160433  PMID: 24618934
sepsis; infant; term birth; infection
5.  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
6.  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
7.  Changes in the Incidence of Candidiasis in Neonatal Intensive Care Units 
Pediatrics  2014;133(2):236-242.
OBJECTIVE:
Neonatal invasive candidiasis is associated with significant morbidity and mortality. We describe the association between invasive candidiasis and changes in use of antifungal prophylaxis, empirical antifungal therapy, and broad-spectrum antibacterial antibiotics over time.
METHODS:
We examined data from 709 325 infants at 322 NICUs managed by the Pediatrix Medical Group from 1997 to 2010. We determined the cumulative incidence of invasive candidiasis and use of antifungal prophylaxis, broad-spectrum antibacterial antibiotics, and empirical antifungal therapy by year.
RESULTS:
We identified 2063 (0.3%) infants with 2101 episodes of invasive candidiasis. Over the study period, the annual incidence of invasive candidiasis decreased from 3.6 episodes per 1000 patients to 1.4 episodes per 1000 patients among all infants, from 24.2 to 11.6 episodes per 1000 patients among infants with a birth weight of 750–999 g, and from 82.7 to 23.8 episodes per 1000 patients among infants with a birth weight <750 g. Fluconazole prophylaxis use increased among all infants with a birth weight <1000 g (or <1500 g), with the largest effect on birth weights <750 g, increasing from 3.8 per 1000 patients in 1997 to 110.6 per 1000 patients in 2010. The use of broad-spectrum antibacterial antibiotics decreased among all infants from 275.7 per 1000 patients in 1997 to 48.5 per 1000 patients in 2010. The use of empirical antifungal therapy increased over time from 4.0 per 1000 patients in 1997 to 11.5 per 1000 patients in 2010.
CONCLUSIONS:
The incidence of invasive candidiasis in the NICU decreased over the 14-year study period. Increased use of fluconazole prophylaxis and empirical antifungal therapy, along with decreased use of broad-spectrum antibacterial antibiotics, may have contributed to this observation.
doi:10.1542/peds.2013-0671
PMCID: PMC3904270  PMID: 24446441
invasive candidiasis; fluconazole prophylaxis; premature infants
8.  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
9.  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
10.  Risk of necrotizing enterocolitis in very-low-birth-weight infants with isolated atrial and ventricular septal defects 
Objective
Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality in premature infants. We sought to identify the frequency of NEC in very-low-birth-weight infants with isolated ventricular septal defects (VSD) or atrial septal defects (ASD) using a large multicenter database.
Methods
We identified a cohort of infants with birth weight <1500 g cared for in 312 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. We examined the association between presence of an ASD or a VSD with development of NEC using logistic regression to control for small-for-gestational-age status, antenatal steroid use, antenatal antibiotic use, gestational age, sex, race, Apgar score at 5 minutes, and method of delivery.
Results
Of the 98,523 infants who met inclusion criteria, 1,904 (1.9%) had an ASD, 1943 (2.0%) had a VSD, and 146 (0.1%) had both. The incidence of NEC was 6.2% in infants without septal defects, 9.3% in those with an ASD, 7.8% in those with a VSD, and 10.3% in infants with both an ASD and a VSD. Compared to infants without septal defects, the adjusted odds ratios for developing NEC for each group—ASD alone, VSD alone, and ASD with VSD—were 1.26 (95% confidence interval 1.06–1.49), 1.27 (1.08–1.52), and 1.80 (1.03–3.12), respectively.
Conclusion
The presence of an ASD or a VSD was associated with NEC in this cohort of premature infants.
doi:10.1038/jp.2013.174
PMCID: PMC3969778  PMID: 24434778
necrotizing enterocolitis; atrial septal defect; ventricular septal defect
11.  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
12.  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
13.  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
14.  Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants 
Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.)
doi:10.1128/AAC.03086-15
PMCID: PMC4862454  PMID: 26926644
15.  Solithromycin Pharmacokinetics in Plasma and Dried Blood Spots and Safety in Adolescents 
We assessed the pharmacokinetics and safety of solithromycin, a fluoroketolide antibiotic, in a phase 1, open-label, multicenter study of 13 adolescents with suspected or confirmed bacterial infections. On days 3 to 5, the mean (standard deviation) maximum plasma concentration and area under the concentration versus time curve from 0 to 24 h were 0.74 μg/ml (0.61 μg/ml) and 9.28 μg · h/ml (6.30 μg · h/ml), respectively. The exposure and safety in this small cohort of adolescents were comparable to those for adults. (This study has been registered at ClinicalTrials.gov under registration no. NCT01966055.)
doi:10.1128/AAC.02561-15
PMCID: PMC4808196  PMID: 26883693
16.  Gaps in Drug Dosing for Obese Children: A Systematic Review of Commonly Prescribed Acute Care Medications 
Clinical therapeutics  2015;37(9):1924-1932.
Purpose
Approximately 1 out of 6 children in the United States is obese. This has important implications for drug dosing and safety, as pharmacokinetic (PK) changes are known to occur in obesity due to altered body composition and physiology. Inappropriate drug dosing can limit therapeutic efficacy and increase drug-related toxicity for obese children. Few systematic reviews examining PK and drug dosing in obese children have been performed.
Methods
We identified 25 acute care drugs from the Strategic National Stockpile and Acute Care Supportive Drugs List and performed a systematic review for each drug in 3 study populations: obese children (2–18 years of age), normal weight children, and obese adults. For each study population, we first reviewed a drug’s Food and Drug Administration (FDA) label, followed by a systematic literature review. From the literature, we extracted drug PK data, biochemical properties, and dosing information. We then reviewed data in 3 age subpopulations (2–7 years, 8–12 years, and 13–18 years) for obese and normal weight children and by route of drug administration (intramuscular, intravenous, by mouth, and inhaled). If sufficient PK data were not available by age/route of administration, a data gap was identified.
Findings
Only 2/25 acute care drugs (8%) contained dosing information on the FDA label for each obese children and adults compared with 22/25 (88%) for normal weight children. We found no sufficient PK data in the literature for any of the acute care drugs in obese children. Sufficient PK data were found for 7/25 acute care drugs (28%) in normal weight children and 3/25 (12%) in obese adults.
Implications
Insufficient information exists to guide dosing in obese children for any of the acute care drugs reviewed. This knowledge gap is alarming, given the known PK changes that occur in the setting of obesity. Future clinical trials examining the PK of acute care medications in obese children should be prioritized.
doi:10.1016/j.clinthera.2015.08.006
PMCID: PMC4586086  PMID: 26323523
obesity; children; pharmacokinetics; acute care
17.  Survival Benefit of Empirical Therapy for Staphylococcus aureus Bloodstream Infections in Infants 
Background
The impact of early adequate empirical antibiotic therapy on outcomes of infants in the neonatal intensive care unit (NICU) who develop Staphylococcus aureus bloodstream infection (BSI) is unknown.
Methods
Infants with S. aureus BSI discharged in 1997–2012 from 348 NICUs managed by the Pediatrix Medical Group were identified. Early adequate empirical antibiotic therapy was defined as exposure to ≥1 antibiotic with anti-staphylococcal activity on the day the first positive blood culture was obtained. All other cases were defined as inadequate empirical antibiotic therapy. We evaluated the association between inadequate empirical antibiotic therapy on outcomes controlling for gestational age, small-for-gestational-age status, gender, discharge year, mechanical ventilation, inotropic support, and use of supplemental oxygen. The primary outcome was 30-day mortality. Secondary outcomes were 7-day mortality, death before hospital discharge, and length of bacteremia.
Results
Of the 3339 infants with S. aureus BSI, 2492 (75%) had methicillin-susceptible S. aureus (MSSA) BSI and 847 (25%) had methicillin-resistant S. aureus (MRSA) BSI. Inadequate empirical antibiotic therapy was administered in 725 (22%) cases. Inadequate empirical antibiotic therapy was associated with increased 30-day mortality (odds ratio, 2.03 [95% confidence interval, 1.08, 3.82]) among infants with MRSA BSI. Inadequate empirical antibiotic therapy was not associated with increases in mortality among infants with MSSA BSI.
Conclusions
After controlling for confounders, inadequate empirical antibiotic therapy was associated with a modestly increased mortality at 30 days for infants with MRSA BSI.
doi:10.1097/INF.0000000000000850
PMCID: PMC4604046  PMID: 26222060
infants; early empirical antibiotic therapy; Staphylococcus aureus bloodstream infection; NICU
18.  Drug Dosing in Obese Children: A Systematic Review of Current Pharmacokinetic Data 
JAMA pediatrics  2015;169(7):678-685.
IMPORTANCE
Obesity affects nearly one sixth of U.S. children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxicity. The depth of available literature regarding obesity’s effect on drug safety, pharmacokinetics (PK) and dosing in obese children is unknown.
OBJECTIVE
To perform a systematic literature review describing the current evidence of the effect of obesity on drug disposition in children.
EVIDENCE REVIEW
We searched the Medline, Cochrane, and Embase databases (January 1970–December 2012) and included studies if they contained clearance, volume of distribution, or drug concentration data in obese children (age ≤18 years). We compared exposure and weight-normalized volume of distribution and clearance between obese and non-obese children. We explored the relationship between drug physicochemical properties and clearance and volume of distribution.
FINDINGS
Twenty studies met inclusion criteria and contained pharmacokinetic data for 21 drugs. The median number of obese children studied per drug was 10 (range 1–112), ages ranged from 0–29 years. Dosing schema varied and were based on a fixed dose (n=6, 29%), body weight (n=10, 48%), and body surface area (n=4, 19%). Clinically significant pharmacokinetic alterations were observed in obese children for 65% (11/17) of studied drugs. Pharmacokinetic alterations resulted in substantial differences in exposure between obese and non-obese children for 38% (5/13) of drugs. We found no association between drug lipophilicity or Biopharmaceutical Drug Disposition Classification System class and changes in volume of distribution or clearance due to obesity.
CONCLUSIONS AND RELEVANCE
Consensus is lacking on the most appropriate weight-based dosing strategy. Prospective pharmacokinetic trials in obese children are needed to ensure therapeutic efficacy and enhance drug safety.
doi:10.1001/jamapediatrics.2015.132
PMCID: PMC4494887  PMID: 25961828
19.  Advances in the treatment of invasive neonatal candidiasis 
Expert opinion on pharmacotherapy  2015;16(7):1035-1048.
Introduction
Invasive candidiasis is responsible for approximately 10% of nosocomial sepsis in very-low-birth-weight (VLBW) infants and is associated with substantial morbidity and mortality. Over the last 2 decades, the antifungal armamentarium against Candida spp. has increased; however, efficacy and safety studies in this population are lacking.
Areas covered
We reviewed the medical literature and extracted information on clinical and observational studies evaluating the use of antifungal agents in neonates with invasive candidiasis.
Expert opinion
Efficacy and safety data for antifungals in neonates are lacking, and the majority of studies conducted to date have concentrated on pharmacokinetic/pharmacodynamic evaluations. Unlike other anti-infective agents, efficacy data in the setting of neonatal candidiasis cannot be extrapolated from adult studies due to differences in the pathophysiology of the disease in this population relative to older children and adults. Data collected thus far or data submitted to regulatory agencies for amphotericin B deoxycholate, fluconazole, and micafungin suggest that these are the current agents of choice for this disease in neonates until data for newer antifungal agents become available. For prophylaxis, data from fluconazole randomized controlled trials will be submitted to the regulatory agencies for labeling. Ultimately, the field of therapeutics for neonatal candidiasis will require multidisciplinary collaboration given the numerous challenges associated with conducting clinical trials in neonates.
doi:10.1517/14656566.2015.1031108
PMCID: PMC4402277  PMID: 25842986
antifungal agents; Candida; echinocandin; invasive candidiasis; neonates; polyene; triazole
20.  Use and safety of erythromycin and metoclopramide in hospitalized infants 
Objective
Prokinetic medications are used in premature infants to promote motility and decrease time to full enteral feeding. Erythromycin and metoclopramide are the most commonly used prokinetic medications in the neonatal intensive care unit (NICU), but their safety profile is not well defined.
Methods
We conducted a large retrospective cohort study using data from 348 NICUs managed by the Pediatrix Medical Group. All infants exposed to ≥1 dose of erythromycin, metoclopramide, or both, from a cohort of 887,910 infants discharged between 1997 and 2012 were included. We collected laboratory and clinical information while infants were exposed to erythromycin or metoclopramide and described the frequency of laboratory abnormalities and clinical adverse events.
Results
Metoclopramide use increased from 1997–2005 and decreased from 2005–2012, while erythromycin use remained stable. Erythromycin use was most often associated with a diagnosis of feeding problem (40%), while metoclopramide was most often associated with a diagnosis of gastroesophageal reflux (59%). The most common laboratory adverse event during exposure to erythromycin or metoclopramide was hyperkalemia (8.6/1000 infant days on erythromycin and 11.0/1000 infant days on metoclopramide). Incidence of pyloric stenosis was greater with erythromycin than with metoclopramide (10/1095, 0.9% vs. 76/19,001, 0.4%, p=0.01), but odds were not significantly increased after adjusting for covariates (odds ratio=0.52 [95% CI: 0.26, 1.02], p=0.06). More infants experienced an adverse event while treated with metoclopramide than with erythromycin (odds ratio=1.21 [95% CI: 1.03, 1.43]).
Conclusion
Metoclopramide was associated with increased risk of adverse events compared to erythromycin. Studies are needed to confirm safety and effectiveness of both drugs in infants.
doi:10.1097/MPG.0000000000000792
PMCID: PMC4553109  PMID: 25806675
21.  Cefepime and Ceftazidime Safety in Hospitalized Infants 
Background
Cefepime and ceftazidime are cephalosporins used for the treatment of serious gram-negative infections. These cephalosporins are used off-label in the setting of minimal safety data for young infants.
Methods
We identified all infants discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012 who were exposed to either cefepime or ceftazidime in the first 120 days of life. We reported clinical and laboratory adverse events occurring in infants exposed to cefepime or ceftazidime and used multivariable logistic regression to compare the odds of seizures and death between the 2 groups.
Results
A total of 1761 infants received 13,293 days of ceftazidime, and 594 infants received 4628 days of cefepime. Laboratory adverse events occurred more frequently on days of therapy with ceftazidime compared with cefepime (373 vs. 341 per 1000 infant days, p<0.001). Seizure was the most commonly observed clinical adverse event, occurring in 3% of ceftazidime-treated infants and 4% of cefepime-treated infants (p=0.52). Mortality was similar between the ceftazidime and cefepime groups (5% vs. 3%, p=0.07). There was no difference in the adjusted odds of seizure (odds ratio [OR] = 0.96 [95% confidence interval, 0.89–1.03]) or the combined outcome of mortality or seizures (OR = 1.00 [0.96–1.04]) in infants exposed to ceftazidime vs. those exposed to cefepime.
Conclusions
In this cohort of infants, cefepime was associated with fewer laboratory adverse events than ceftazidime, although this may have been due to a significant difference in clinical exposures and severity of illness between the 2 groups. There was no difference in seizure risk or mortality between the 2 drugs.
doi:10.1097/INF.0000000000000778
PMCID: PMC4573537  PMID: 26376308
22.  Neonatal Escherichia coli Bloodstream Infections: Clinical Outcomes and Impact of Initial Antibiotic Therapy 
Background
Escherichia coli is a common cause of bloodstream infections (BSI) in infants and is associated with high mortality and morbidity among survivors. The clinical significance of antibiotic resistance and timing of appropriate antimicrobial therapy in this population is poorly understood.
Methods
We identified all infants with E. coli BSIs discharged from 77 neonatal intensive care units managed by the Pediatrix Medical Group in 2012. We used multivariable logistic regression to evaluate the association between 30-day mortality and ampicillin-resistant E. coli BSI, as well as the number of active empiric antimicrobial agents administered, controlling for gestational age, small-for-gestational age status, early- versus late-onset BSI, oxygen requirement, ventilator support, and inotropic support on the day of the first positive blood culture.
Results
We identified 258 episodes of E. coli BSI, including 123 (48%) ampicillin-resistant isolates. Unadjusted 30-day mortality did not significantly differ between infants with ampicillin-resistant vs. -susceptible E. coli BSI (11/123 [9%] vs. 7/135 [5%]; p=0.33; adjusted odds ratio=1.37 [95% confidence interval 0.39, 4.77]). Among ampicillin-resistant E. coli BSIs, 30-day mortality was not significantly lower for infants treated with at least one empiric antimicrobial active against ampicillin-resistant E. coli vs. infants receiving no active empiric agent (adjusted odds ratio=1.50 [0.07, 33.6]).
Conclusions
In this population of infants with E. coli BSI, ampicillin resistance was not associated with significantly increased mortality. Among the subset of infants with ampicillin-resistant E. coli, appropriate empirical antibiotic therapy was not associated with lower mortality.
doi:10.1097/INF.0000000000000769
PMCID: PMC4581845  PMID: 26065862
Escherichia coli; antimicrobial resistance; early-onset sepsis; late-onset sepsis; bacteremia
23.  The Epidemiology and Diagnosis of Invasive Candidiasis Among Premature Infants 
Clinics in perinatology  2014;42(1):105-117.
Invasive candidiasis is a leading infectious cause of morbidity and mortality in premature infants. Improved recognition of modifiable risk factors and antifungal prophylaxis have contributed to the recent decline in the incidence of this infection among infants. Invasive candidiasis typically occurs in the first six weeks of life and presents with non-specific signs of sepsis. Definitive diagnosis relies on growth of Candida in blood culture or cultures from other normally sterile sites, but this may identify fewer than half of cases. Improved diagnostics are needed to guide initiation of antifungal therapy in premature infants.
doi:10.1016/j.clp.2014.10.008
PMCID: PMC4328135  PMID: 25677999
neonatal candidiasis; Candida; premature infants; risk factors
24.  Medication use in the neonatal intensive care unit 
American journal of perinatology  2013;31(9):811-822.
Objective
We provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time.
Study Design
We performed a retrospective review (2005–2010) of a large prospectively collected administrative database.
Result
Medications most commonly administered during the study period were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (56–681 exposures per 1000 infants). Those with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Medications with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram.
Conclusion
Medication use in the NICU has changed substantially over time, and only 35% of the most commonly prescribed medications are FDA-approved in infants.
doi:10.1055/s-0033-1361933
PMCID: PMC4061287  PMID: 24347262
pharmacotherapy; trends over time
25.  Rifampin Use and Safety in Hospitalized Infants 
American journal of perinatology  2015;32(6):565-570.
Objective
To examine the use and safety of rifampin in hospitalized infants.
Study Design
Observational study of clinical and laboratory adverse events among infants exposed to rifampin from 348 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012.
Result
2500 infants received 4279 courses of rifampin; mean gestational age was 27 weeks (5th, 95th %tile; 23, 36) and mean birth weight was 1125 g (515, 2830). Thrombocytopenia (121/1000 infant days) and conjugated hyperbilirubinemia (25/1000 infant days) were the most common laboratory adverse events. The most common clinical adverse events were medical necrotizing enterocolitis (64/2500 infants, 3%) and seizure (60/2500 infants, 2%).
Conclusion
The overall incidence of adverse events among infants receiving rifampin appears low; however, additional studies to further evaluate safety and dosing of rifampin in this population are needed.
doi:10.1055/s-0034-1543955
PMCID: PMC4433596  PMID: 25594217
rifampin; broad-spectrum antibiotic; infectious disease; neonatal intensive care unit

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