Carbapenems are commonly used in hospitalized infants despite a lack of complete safety data and associations with seizures in older children. We compared the incidence of adverse events in hospitalized infants receiving meropenem versus imipenem/cilastatin.
We conducted a retrospective cohort study of 5566 infants treated with meropenem or imipenem/cilastatin in neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. Multivariable conditional logistic regression was performed to evaluate the association between carbapenem therapy and adverse events, controlling for infant factors and severity of illness.
Adverse events were more common with use of meropenem compared with imipenem/cilastatin (62.8/1000 infant days vs. 40.7/1000 infant days, P<0.001). There was no difference in seizures with meropenem vs. imipenem/cilastatin (adjusted odds ratio [OR] 0.96; 95% confidence interval 0.68, 1.32). The incidence of death, as well as the combined outcome of death or seizure, was lower with meropenem use—OR 0.68 (0.50, 0.88) and OR 0.77 (0.62, 0.95), respectively.
In this cohort of infants, meropenem was associated with more frequent but less severe adverse events when compared with imipenem/cilastatin.
meropenem; imipenem/cilastatin; adverse events; infant
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.
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.
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.
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.
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.
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.
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.
In our cohort, the incidence of early-onset GBS SBI decreased, while the incidence of late-onset SBI for E. coli and GBS increased.
infection; infant; sepsis; group B Streptococcus; Escherichia coli
We describe the incidence, risk factors, and outcomes of invasive candidiasis in infants >1500 g birth weight.
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.
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]).
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.
candidiasis; candidemia; neonates; neonatal intensive care unit
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.
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.
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.
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.
neonatal; early-onset sepsis; blood cell count
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.
We evaluated the diagnostic accuracy of the complete blood count and differential in late-onset sepsis in a large multicenter population.
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.
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).
No complete blood count index possessed adequate sensitivity to reliably rule out late-onset sepsis in this population.
neonatal; late-onset sepsis; blood cell count
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.
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.
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).
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.
invasive candidiasis; infants; amphotericin B deoxycholate; fluconazole; amphotericin B lipid products
Very-low-birth-weight (VLBW, <1500 g birth weight) infants are at high risk for both early- and late-onset sepsis. Prior studies have observed a predominance of gram-negative organisms as a cause of early-onset sepsis and gram-positive organisms as a cause of late-onset sepsis. These reports are limited to large, academic neonatal intensive care units (NICUs) and may not reflect findings in other units. The purpose of this study was to determine the risk factors for sepsis, the causative organisms, and mortality following infection in a large and diverse sample of NICUs.
We analyzed the results of all cultures obtained from VLBW infants admitted to 313 NICUs from 1997 to 2010.
Over 108,000 VLBW infants were admitted during the study period. Early-onset sepsis occurred in 1032 infants, and late-onset sepsis occurred in 12,204 infants. Gram-negative organisms were the most commonly isolated pathogens in early-onset sepsis, and gram-positive organisms were most commonly isolated in late-onset sepsis. Early- and late-onset sepsis were associated with increased risk of death controlling for other confounders (odds ratio 1.45 [95% confidence interval 1.21, 1.73], and OR 1.30 [95% CI 1.21, 1.40], respectively).
This is the largest report of sepsis in VLBW infants to date. Incidence for early-onset sepsis and late-onset sepsis has changed little over this 14-year period, and overall mortality in VLBW infants with early- and late-onset sepsis is higher than in infants with negative cultures.
early-onset sepsis; late-onset sepsis; very-low-birth-weight infants
We sought to describe the incidence, pathogen distribution, and mortality associated with blood culture-proven sepsis in young infants with congenital heart disease (CHD) admitted to a neonatal intensive care unit (NICU).
Cohort study of all blood cultures obtained from infants with CHD between 4 and 120 days of age cared for in250 NICUs managed by the Pediatrix Medical Group in the United States between 1996 and 2007.
Of 11,638 infants with CHD, 656 (6%) had 821 episodes of sepsis: a cumulative incidence of 71/1000 admissions. Gram-positive organisms were the most common cause (64%), and coagulase-negative Staphylococcus and Staphylococcus aureus were the most frequently isolated species. On multivariable regression, infants with sepsis were more likely to die compared to infants with sterile blood cultures (odds ratio [OR] = 1.53 [95% confidence interval: 1.09, 2.13]). Infants with gram-negative bacteremia and candidemia were more likely to die than infants with sterile blood cultures (OR = 2.01 [1.20, 3.37], and OR = 3.18 [1.60, 6.34], respectively).
Infants with CHD have a high incidence of culture-proven sepsis, especially with staphylococcal organisms. Gram-negative bacteremia and candidemia are strongly associated with increased mortality in this group of young infants.
infant; sepsis; infection; congenital heart disease; epidemiology; outcomes
Perinatal brain injury; cerebral palsy; resuscitation; hypothermia; hypoxic-ischemic encephalopathy; biomarker
Necrotizing enterocolitis is associated with high morbidity and mortality among infants admitted for intensive care. The factors associated with mortality and catastrophic presentation remain poorly understood.
To describe the factors associated with mortality in infants with necrotizing enterocolitis and to quantify the degree to which catastrophic presentation contributes to mortality in infants with necrotizing enterocolitis.
We performed a retrospective review of the Pediatrix's Clinical Data Warehouse (1997-2009) to compare the demographic, therapeutic and outcome characteristics of infants who survived NEC versus those who died. Associations were tested by bivariate and multivariate analysis.
In a total cohort of 560,227 infants, there were 2661 cases (17%) of surgically treated and 6460 (42%) of medically treated necrotizing enterocolitis; 1505 (16.5%) died. In multivariate analysis, the factors associated with death (P<0.01 in analysis) were lower estimated gestational age, lower birth weight, a need for assisted ventilation on the day of diagnosis of NEC, a need for vasopressors at the time of diagnosis, and Black race. Patients who received only ampicillin and gentamicin on the day of diagnosis were less likely to die.
Two thirds of NEC deaths occurred quickly (<7 days from diagnosis), with a median time of death of one day from time of diagnosis. Infants who died within 7 days of diagnosis had a higher birth weight, more often required vasopressors and more often were treated with high frequency ventilation at the time of diagnosis compared to patients who died at 7 or more days. Although mortality decreased with increasing gestational age, the proportion of deaths that occur within 7 days was relatively consistent (65-75 percent of the patients who died) across all gestational ages.
Mortality among infants who have necrotizing enterocolitis remains high and infants who die of necrotizing enterocolitis commonly (66%) die quickly. Most of the factors associated with mortality are related to immaturity, low birth weight and severity of illness.
Coagulase-negative staphylococci (CoNS) are the most commonly isolated pathogens in the neonatal intensive care unit (NICU). CoNS infections are associated with increased morbidity including neurodevelopmental impairment.
Describe the epidemiology of CoNS infections in the NICU. Determine mortality among infants with definite, probable, or possible CoNS infections.
We performed a retrospective cohort study of all blood, urine, and cerebrospinal fluid cultures from infants <121 postnatal days.
248 NICUs managed by the Pediatrix Medical Group from 1997 to 2009.
We identified 16,629 infants with 17,624 episodes of CoNS infection: 1734 (10%) definite, 3093 (17%) probable, and 12,797 (73%) possible infections. Infants with lower gestational age and birth weight had a higher incidence of CoNS infection. Controlling for gestational age, birth weight, and 5-minute Apgar score, infants with definite, probable, or possible CoNS infection had lower mortality—OR=0.74 (95% confidence interval; 0.61, 0.89), OR= 0.68 (0.59, 0.79), and OR=0.69 (0.63, 0.76)—compared to infants with negative cultures (P<0.001). No significant difference in overall mortality was found in infants with definite CoNS infection compared to those with probable or possible CoNS infection—OR=0.93 (0.75, 1.16) and OR=0.85 (0.70, 1.03), respectively.
CoNS infection was strongly related to lower gestational age and birth weight. Infants with clinical sepsis and culture-positive CoNS infection had lower mortality rates than infants with clinical sepsis and negative blood culture results. No difference in mortality between infants diagnosed with definite, probable, or possible CoNS infection was observed.
nosocomial infection; infant; prematurity; Staphylococcus
The purpose of this study is to examine the results of repeat lumbar puncture in infants with initial positive cerebrospinal fluid (CSF) cultures in order to determine the clinical characteristics and outcomes of infants with repeat positive cultures.
Cohort study of infants with an initial positive CSF culture undergoing repeat lumbar puncture between 1997 and 2004 at 150 neonatal intensive care units managed by the Pediatrix Medical group. We compared the clinical outcomes of infants with repeat positive cultures and infants with repeat negative cultures.
We identified 118 infants with repeat CSF cultures. Of these, 26 infants had repeat positive cultures. A higher proportion with repeat positive cultures died compared to those with repeat negative cultures, 6/23 (26%) vs. 6/81 (7%), respectively (p=0.02).
Among infants with a positive CSF culture, a repeat positive CSF culture is common. The presence of a second positive culture is associated with increased mortality.
neonate; newborn; cerebrospinal fluid; infection; mortality
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.
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.
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).
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.
blood culture; neonate; prematurity; infection; near term
Describe cerebrospinal fluid parameters in infants with culture-proven Group B streptococcal meningitis in the era of intrapartum antibiotic prophylaxis.
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.
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.
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.
Group B streptococcus; intrapartum antibiotic prophylaxis; meningitis
Cerebrospinal fluid (CSF) findings are often used to diagnose meningitis in neonates given antibiotics before the lumbar puncture is performed. Traumatic lumbar punctures are common and complicate interpretation of CSF white blood cell counts. The purpose of this study is to evaluate the diagnostic utility of adjusting CSF white blood cell counts based on CSF and peripheral red blood cell counts.
Cohort study of lumbar punctures performed between 1997 and 2004 at 150 neonatal intensive care units managed by the Pediatrix Medical group. Traumatic lumbar punctures were defined as CSF specimens with ≥500 red blood cells/mm3. CSF white blood cell counts were adjusted downward for traumatic lumbar punctures using several commonly used methods. We calculated sensitivity, specificity, likelihood ratios, and area under the receiver operating characteristic curve of unadjusted and adjusted CSF white blood cell counts for predicting meningitis in neonates with traumatic lumbar punctures.
Of 6,374 lumbar punctures, 2,519 (39.5%) were traumatic. 114/6,374 (1.8%) were positive for meningitis; 50 neonates with traumatic lumbar punctures had meningitis. The areas under the receiver operating characteristic curve for white blood cell count unadjusted and adjusted by all methods were similar.
Adjustment of CSF white blood cell counts to account for increased red cells does not improve diagnostic utility. Adjustment can result in loss of sensitivity with marginal gain in specificity. Adjustment of WBC counts in the setting of a traumatic lumbar puncture does not aid in the diagnosis of bacterial and fungal meningitis in neonates.
diagnosis; meningitis; neonate
Cerebrospinal fluid parameters are of great importance in diagnosing meningitis, but normal values for preterm neonates are based on small, single-center studies. We sought to determine current values for preterm neonate cerebrospinal fluid parameters and assess the association of cerebrospinal fluid parameters with culture proven meningitis.
Cohort study of the first lumbar puncture from 4,632 neonates <34 weeks gestation performed in the years 1997-2004 at 150 neonatal intensive care units managed by the Pediatrix Medical Group.
We identified 95 cases of meningitis from the 4,632 lumbar punctures. The area under the receiver operating characteristic curves for white blood cell count, glucose, and protein were 0.80, 0.63, and 0.72 respectively for prediction of culture proven meningitis.
Cerebrospinal fluid parameters used to diagnose meningitis in the absence of dependable cerebrospinal fluid cultures are unreliable. Caution should be employed when interpreting cerebrospinal fluid parameters in the premature neonate.
nosocomial infections; central nervous system; diagnosis; preterm
When used during extracorporeal membrane oxygenation (ECMO), jugular venous bulb catheters, known as cephalad cannulae, increase venous drainage, augment circuit flow and decompress cerebral venous pressure. Optimized cerebral oxygen delivery during ECMO may contribute to a reduction in neurological morbidity. This study describes the use of cephalad cannulae and identifies rudimentary data for jugular venous oxygen saturation (JVO2) and arterial to jugular venous oxygen saturation difference (AVDO2) in this patient population.
Patients on venoarterial (VA) ECMO displayed higher JVO2 (P < 0.01) and lower AVDO2 (P = 0.01) than patients on venovenous (VV) ECMO (P < 0.01). During VV ECMO, JVO2 was higher and AVDO2 lower when systemic pH was < 7.35 rather than > 7.4 (P = 0.01). During VA ECMO, similar differences in AVDO2 but not in JVO2 were observed at different pH levels (P = 0.01).
Jugular venous saturation and AVDO2 were influenced by systemic pH, ECMO type and patient age. These data provide the foundation for normative values of JVO2 and AVDO2 in neonates and children treated with ECMO.
extracorporeal membrane oxygenation; venovenous ECMO; venoarterial ECMO; cephalad cannulae; jugular venous oxygen content
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.
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.
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%).
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.
Neonate; VLBW; sepsis; late onset