Jessica E. Ericson

Burden of Invasive Staphylococcus aureus Infections in Hospitalized Infants

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. OBJECTIVES To compare demographics and mortality of infants with invasive methicillin-resistant S aureus (MRSA) and methicillin-susceptible S aureus (MSSA), to determine the annual proportion of S aureus infections that were MRSA, and to contrast the risk of death after an invasive MRSA infection with the risk after an invasive MSSA infection. DESIGN, SETTING, AND PARTICIPANTS Multicenter retrospective study of a large, nationally representative cohort at 348 neonatal intensive care units managed by the Pediatrix Medical Group. Participants were 3888 infants with an invasive S aureus infection who were discharged from calendar year 1997 through calendar year 2012. EXPOSURE Invasive S aureus infection. MAIN OUTCOMES AND MEASURES The incidence of invasive S aureus infections, as well as infant characteristics and mortality after MRSA or MSSA infection. RESULTS The 3888 infants had 3978 invasive S aureus infections (2868 MSSA and 1110 MRSA). The incidence of invasive S aureus infection was 44.8 infections per 10,000 infants. The yearly proportion of invasive infections caused by MRSA increased from calendar year 1997 through calendar year 2006 and has moderately decreased 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 (n = 237) died before hospital discharge than infants with invasive MRSA infections (n = 110). The proportions of infants who died after invasive MSSA and MRSA infections were similar at 237 of 2474 (9.6%) and 110 of 926 (11.9%), respectively (P = .05). The adjusted risk of death before hospital discharge was similar after invasive MSSA and MRSA infections (risk ratio, 1.19; 95% CI, 0.96-1.49). The risks of death at 7 and 30 days after invasive infection were similar between infants with invasive MSSA infection and infants with invasive MRSA infection. CONCLUSIONS AND RELEVANCE Infant mortality after invasive MRSA and MSSA infections is similar, but MSSA causes more infections and more deaths in infants than MRSA. Measures to prevent S aureus infection should include MSSA in addition to MRSA.

Chorioamnionitis : Implications for the Neonate

Chorioamnionitis (CA) is characterized by inflammation of the fetal membranes. The incidence increases with decreasing gestational age at birth. When suspected on clinical criteria, pathologic assessment of the placenta should be performed. Although the mechanisms are not entirely clear, CA predisposes to premature birth, neonatal sepsis, and intraventricular hemorrhage. Its role in respiratory distress syndrome, bronchopulmonary dysplasia, and neurodevelopmental impairment is mixed. Prevention and treatment are ill-defined; antibiotics for preterm premature rupture of membranes reduce the incidence and increase the length of time to delivery. Antibiotics are recommended for infants exposed to CA while laboratory studies are being performed.

No survival benefit with empirical vancomycin therapy for coagulase-negative staphylococcal bloodstream infections in infants.

Background: Coagulase-negative Staphylococcus (CoNS) is the most common cause of bloodstream infections (BSI) in hospitalized infants. CoNS BSI is most reliably treated with vancomycin; however, concerns about side effects and promoting resistance often delay empirical vancomycin therapy until culture results become available. Methods: All infants with CoNS BSI discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group from 1997 to 2012 were identified. Empirical vancomycin therapy was defined as vancomycin exposure on the day of the first positive blood culture. Delayed vancomycin therapy was defined as vancomycin exposure 1–3 days after the first positive blood culture. We used multivariable logistic regression with random effects for site to evaluate the association between the use of empirical vancomycin therapy versus delayed vancomycin therapy and 30-day mortality, controlling for gestational age, small-for-gestational age status, postnatal age on the day of the first positive culture, oxygen requirement, ventilator support and inotropic support on the day the first positive culture was obtained. Results: A total of 4364 infants with CoNS BSI were identified; 2848 (65%) were treated with empirical vancomycin. The median postnatal age at first positive culture was 14 days (interquartile range: 9, 21). Unadjusted 30-day mortality was similar for infants treated with empirical vancomycin and infants treated with delayed vancomycin therapy [166/2848 (6%) vs. 69/1516 (4%); P = 0.08]. There was no significant difference in 30-day mortality on multivariable analysis [odds ratio: 1.14 (0.84, 1.56)]. The median duration of bacteremia was 1 day longer for infants with delayed vancomycin therapy [4 days (interquartile range: 2, 6) vs. 3 days (2, 5); P < 0.0001]. Conclusions: The median duration of bacteremia was 1 day longer in infants with CoNS BSI who received delayed vancomycin therapy. Despite this finding, empirical vancomycin therapy for CoNS BSI was not associated with improved mortality.

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 infections (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.

Neonatal Escherichia coli Bloodstream Infections: Clinical Outcomes and Impact of Initial Antibiotic Therapy.

Background: Escherichia coli is a common cause of bloodstream infections (BSIs) 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-onset 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 versus ampicillin-susceptible E. coli BSI [11 of 123 (9%) vs. 7 of 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 versus 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.

Fluconazole prophylaxis for prevention of invasive candidiasis in infants

Purpose of review Invasive candidiasis is a serious infection in hospitalized infants that results in significant mortality and morbidity. Fluconazole is approved by the US Food and Drug Administration for prophylaxis of invasive candidiasis in patients undergoing bone marrow transplantation but is not approved for use in infants. This review will describe the history of fluconazole use for prophylaxis in infants. Recent findings Limiting fluconazole prophylaxis to infants with risk factors, in addition to low birth weight and early gestational age, reduces the number of infants treated with fluconazole and the duration of fluconazole therapy for each infant. Summary Fluconazole prophylaxis appears to be well tolerated for use in premature infants. Reduction in the incidence of invasive candidiasis is observed even when prophylaxis is limited to infants with multiple risk factors. Centers with a low incidence of invasive candidiasis may not benefit from fluconazole prophylaxis. Significant short-term and long-term toxicity and increases in fluconazole-resistant organisms have not been observed with fluconazole use in the intensive care nursery.

Electronic Health Records and Pharmacokinetic Modeling to Assess the Relationship between Ampicillin Exposure and Seizure Risk in Neonates

OBJECTIVE To evaluate the relationship between ampicillin dosing, exposure, and seizures. STUDY DESIGN This was a retrospective observational cohort study of electronic health record (EHR) data combined with pharmacokinetic model derived drug exposure predictions. We used the EHR from 348 Pediatrix Medical Group neonatal intensive care units from 1997 to 2012. We included all infants 24-41 weeks gestational age, 500-5400 g birth weight, first exposed to ampicillin prior to 25 days postnatal age. Using a 1-compartment pharmacokinetic model and EHR data, we simulated maximum ampicillin concentration at steady state (Cmaxss, µg/mL) and area under the concentration time curve from 0 to 24 hours (AUC24, µg*h/dL). Using multivariable logistic regression, we evaluated association between ampicillin dosing, exposure, and seizures as documented in the EHR. RESULTS We identified 131 723 infants receiving 134 041 courses of ampicillin for 653 506 infant-days of exposure. The median daily dose was 200 mg/kg/d (25th, 75th percentile; 100, 200). Median Cmaxss and AUC24 were 256.6 µg/mL (164.3, 291.5) and 2593 µg*h/dL (1917, 3334). On multivariable analysis, dosing was not associated with seizures. However increasing Cmaxss (OR = 1.10, 95% CI 1.03, 1.17) and AUC24 (OR 1.11, 95% CI 1.05, 1.18) were associated with increased odds of seizures. CONCLUSIONS In this cohort of hospitalized infants, higher ampicillin exposure was associated with seizures as documented in the EHR.

Fluconazole Prophylaxis for the Prevention of Candidiasis in Premature Infants: A Meta-analysis Using Patient-level Data

BACKGROUND Invasive candidiasis (IC) is an important cause of sepsis in premature infants and is associated with a high risk of death and neurodevelopmental impairment. Prevention of IC has become a major focus in very low birth weight infants, with fluconazole increasingly used as prophylaxis. METHODS We identified all randomized, placebo-controlled trials evaluating fluconazole prophylaxis in premature infants conducted in the United States. We obtained patient-level data from the study investigators and performed an aggregated analysis. The occurrence of each endpoint in infants who received prophylaxis with fluconazole vs placebo was compared. Endpoints evaluated were IC or death, IC, death, Candida colonization, and fluconazole resistance among tested isolates. Safety endpoints evaluated included clinical and laboratory parameters. RESULTS Fluconazole prophylaxis reduced the odds of IC or death, IC, and Candida colonization during the drug exposure period compared with infants given placebo: odds ratios of 0.48 (95% confidence interval [CI], .30-.78), 0.20 (95% CI, .08-.51), and 0.28 (95% CI, .18-.41), respectively. The incidence of clinical and laboratory adverse events was similar for infants who received fluconazole compared with placebo. There was no statistically significant difference in the proportion of tested isolates that were resistant to fluconazole between the fluconazole and placebo groups. CONCLUSIONS Fluconazole prophylaxis is effective and safe in reducing IC and Candida colonization in premature infants, and has no impact on resistance.

Old and new: appropriate dosing for neonatal antifungal drugs in the nursery.

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.

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 of the infants exposed to ≥1 dose of erythromycin, metoclopramide, or both, from a cohort of 8,87,910 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 (AEs). Results: Metoclopramide use increased from 1997 to 2005 and decreased from 2005 to 2012, whereas erythromycin use remained stable. Erythromycin use was most often associated with a diagnosis of feeding problem (40%), whereas metoclopramide was most often associated with a diagnosis of gastroesophageal reflux (59%). The most common laboratory AE 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% confidence interval [CI] 0.26–1.02, P = 0.06). More infants experienced an AE while treated with metoclopramide than with erythromycin (odds ratio 1.21, 95% CI 1.03–1.43). Conclusions: Metoclopramide was associated with increased risk of AEs compared with erythromycin. Studies are needed to confirm safety and effectiveness of both the drugs in infants.