Short-course antibiotic therapy for pneumonia in the neonatal intensive care unit.

OBJECTIVE: To determine the adherence and safety outcomes of a 5-day antibiotic course with a "time-out" for treatment of "blood culture-negative" pneumonia in the NICU. STUDY DESIGN: Prospective surveillance of all infants diagnosed with pneumonia at 7 NICUs from 8/2020-12/2021. Safety outcomes were defined a priori by re-initiation of antibiotic therapy within 14 days after discontinuation and overall and sepsis-related mortality. RESULTS: 128 infants were diagnosed with 136 episodes of pneumonia; 88% (n = 119) were treated with 5 days of definitive antibiotic therapy. Antibiotics were restarted within 14 days in 22 (16%) of the 136 pneumonia episodes. However, only 3 (3%) of the 119 episodes of pneumonia treated for 5 days had antibiotics restarted for pneumonia. Mortality was 5% (7/128); 5 of the 7 deaths were assessed as sepsis-related. CONCLUSION: Adherence to the 5-day definitive antibiotic treatment for "culture-negative" pneumonia was high and the intervention seemed safe.

Short-course empiric antibiotic therapy for possible early-onset sepsis in the NICU.

OBJECTIVE: On 2/2019, the Neonatal Antimicrobial Stewardship Program at Nationwide Children's Hospital recommended reducing empirical antibiotic therapy for early-onset sepsis (EOS) from 48 to 24 hours with a TIME-OUT. We describe our experience with this guideline and assess its safety. METHODS: Retrospective review of newborns evaluated for possible EOS at 6 NICUs from 12/2018-7/2019. Safety endpoints were re-initiation of antibiotics within 7 days after discontinuation of the initial course, positive bacterial blood or cerebrospinal fluid culture in the 7 days after antibiotic discontinuation, and overall and sepsis-related mortality. RESULT: Among 414 newborns evaluated for EOS, 196 (47%) received a 24 hour rule-out sepsis antibiotic course while 218 (53%) were managed with a 48 hour course. The 24-hour rule-out group were less likely to have antibiotics re-initiated and did not differ in the other predefined safety endpoints. CONCLUSION: Antibiotic therapy for suspected EOS may be discontinued safely within 24 hours.

Effects of prophylactic indomethacin on intraventricular hemorrhage and adverse outcomes in neonatal intensive care unit.

OBJECTIVE: To identify the relationship between prophylactic indomethacin (PI) administration and incidence of intraventricular hemorrhage. STUDY DESIGN: A retrospective analysis of extremely premature infants <27 weeks gestational age born between January 2014 and September 2020. RESULTS: A total of 421 infants were included from three of Nationwide Children's Hospital delivery centers. Of those 255 (61%) received PI. After adjustment by inverse proportionality treatment weighting (IPTW), no differences were found in incidence of intraventricular hemorrhage (IVH) at the time of the first ultrasound, 31% vs. 33% in PI and control groups respectively (p = 0.68). The rate of rise of serum creatinine from baseline to day of life four was significantly higher in the PI group (0.14 mg/dl PI and 0.03 mg/dl control, p < 0.001). CONCLUSION: PI was not associated with any benefit in prevention of IVH, but is associated with adverse effects including acute rise in creatinine.

Global resilience and new strategies needed for antimicrobial stewardship during the COVID-19 pandemic and beyond.

Resilience is having the ability to respond to adversity proactively and resourcefully. The coronavirus disease 2019 (COVID-19) pandemic's profound impact on antimicrobial stewardship programs (ASP) requires clinicians to call on their own resilience to manage the demands of the pandemic and the disruption of ASP activities. This article provides examples of ASP resilience from pharmacists and physicians from seven countries with different resources and approaches to ASP-The United States, The United Kingdom, Canada, Nigeria, Lebanon, South Africa, and Colombia. The lessons learned pertain to providing ASP clinical services in the context of a global pandemic, developing new ASP paradigms in the face of COVID-19, leveraging technology to extend the reach of ASP, and conducting international collaborative ASP research remotely. This article serves as an example of how resilience and global collaboration is sustaining our ASPs by sharing new "how to" do antimicrobial stewardship practices during the COVID-19 pandemic.

Safety and Efficacy of Nafcillin for Empiric Therapy of Late-Onset Sepsis in the NICU.

BACKGROUND AND OBJECTIVE: In 2014 at Nationwide Children's Hospital, the Neonatal Antimicrobial Stewardship Program recommended nafcillin over vancomycin for empirical therapy of possible late-onset sepsis (LOS) in infants without a history of methicillin-resistant Staphylococcus aureus colonization or infection. We report our experience with this guideline and assess its safety. METHODS: We retrospectively reviewed all infants who received nafcillin or vancomycin for empirical treatment of possible LOS at 3 NICUs before (January 2013-May 2014) and after (January 2017-March 2019) implementation of a vancomycin reduction guideline. Safety measures included duration of blood culture positivity, recurrence of infection with the same previously identified pathogen in the 14 days after discontinuation of antibiotic therapy, and mortality. RESULTS: Among 366 infants who received a first antibiotic course for possible LOS, 84% (95 of 113) and 25% (62 of 253) received empirical therapy with vancomycin before and after the guideline implementation, respectively, representing a 70% reduction. Nafcillin use increased by 368%. Duration of blood culture positivity did not differ before and after the guidance. In 2 infants, antibiotic therapy was restarted within 14 days of discontinuation of the initial therapy for recurrence of the same infection; both had received empirical vancomycin. Overall in-hospital mortality was 10%, and there was no difference before (9%) and after (10%) implementation of the vancomycin reduction guidance (odds ratio, 0.97). CONCLUSIONS: Nafcillin can be a safe alternative to vancomycin for empirical therapy of LOS among NICU infants who do not have a history of methicillin-resistant S aureus infection or colonization.

Nephrotoxic medications and associated acute kidney injury in hospitalized neonates.

OBJECTIVES: Hospitalized neonates are often treated with nephrotoxic medications, a known risk factor for acute kidney injury (AKI). Nephrotoxic medications and AKI, especially in periviable neonates, could be detrimental to nephrogenesis. Our objectives were to evaluate the prevalence of neonatal treatment with nephrotoxic medications and its relationship with AKI in in the first 28 days of life, and to delineate the associated demographics and diagnoses. STUDY DESIGN: Multicenter retrospective analysis using the national Pediatric Hospital Information System database, including 49 pediatric hospitals. Neonates admitted within the first two postnatal days were included. Treatment with 37 nephrotoxic medications across demographics and clinical variables, and relationship with AKI were evaluated. AKI was determined by using the International Classification of Diseases codes. RESULTS: Of 192,229 neonates, 74% were treated with at least one nephrotoxic medication. Incidence of AKI was significantly higher in the treated group (aRR 3.68 [95% CI: 2.85, 4.75]). The aRRs of treatment were increased in infants born < 32-week, and < 2000 g. Nephrotoxic medications were prescribed to 90-95% of neonates born ≤ 28-week gestational age. Most treatments (95-98%) occurred in the first 3 days. Intravascular aminoglycosides were the most frequent type; 28% of neonates were treated for ≥ 4 calendar days. Most common diagnoses were infections (25%) and patent ductus arteriosus (20%). CONCLUSIONS: Neonatal treatment with nephrotoxic medications is common, especially among the smallest, most immature preterm neonates and demonstrates a need for initiatives to reduce neonatal exposure to these agents, when feasible. Across all gestational age categories, the prevalence of AKI is higher in the neonates treated with nephrotoxic drugs. The long-term effects of treatment with nephrotoxic medications and subsequent AKI on nephrogenesis and nephron endowment will need to be evaluated.

Biochemical Parameters in Extremely Preterm Infants Receiving Mixed Lipid Emulsions.

OBJECTIVE: A mixture of soybean, medium-chain triglycerides, olive, and fish oils (SMOF) contains higher α-tocopherol and n-3 polyunsaturated fatty acids and lower phytosterol content compared with conventional soybean oil lipid emulsions (SOLE). We sought to characterize plasma total fatty acid profiles (FAPs) and assess the tolerability of long-term SMOF therapy in extremely preterm infants. METHODS: We retrospectively evaluated infants born <28 weeks gestational age who received at least 30 consecutive days of SMOF between July 2016 and June 2019. We evaluated monthly FAPs and biochemical tolerance to SMOF using direct bilirubin (DB) and triglyceride (TG) levels. Growth parameters were evaluated longitudinally until discharge. RESULTS: Sixteen patients with median gestational age 24 weeks (IQR, 23-25 weeks) received SMOF for median 76 days (IQR, 52-130 days). Fourteen patients had necrotizing enterocolitis (NEC) requiring surgical intervention and 15 patients received SOLE for median 19 days (IQR, 14-26 days) prior to switching to SMOF. Median docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels were elevated, whereas the remaining fatty acid levels fell within reported reference ranges. There were no incidents of essential fatty acid deficiency (triene to tetraene ratio >0.2) or hypertriglyceridemia (TG >200 mg/dL) with a general downtrend in DB after the first month on SMOF. All growth Z-scores declined throughout hospital stay. CONCLUSIONS: Infants who received SMOF had a more pronounced elevation in DHA than EPA, of which the clinical significance remains unknown. Growth Z-scores declined with SMOF but were confounded by a high prevalence of surgically treated NEC.

Neonatal Abstinence Syndrome and Preterm Infants: A Look at Current Practice.

BACKGROUND/SIGNIFICANCE: Intrauterine opioid drug exposure is associated with an increased risk of preterm birth. Preterm infants may not exhibit the same withdrawal symptoms as term infants diagnosed with neonatal abstinence syndrome (NAS). There are no current standards for how to screen, assess, or treat NAS in preterm infants. PURPOSE: This study explored the current state of practice for preterm infants born at less than 34 weeks of gestational age exposed to intrauterine opioids. METHODS: This was a descriptive cross-sectional study of NAS practice in preterm infants born at less than 34 weeks of gestational age in neonatal intensive care units (NICUs) in the United States and Canada. The study was conducted May through September 2018. All respondents cared for preterm infants born at less than 34 weeks of gestational age exposed to intrauterine drugs. RESULTS: There were 70 respondents representing 67 hospitals in the United States and 1 in Canada. Level III NICUs represented 69% of respondents. Ninety-three percent reported neonatal triggers for further evaluation. Review of maternal history and maternal urine testing was the most consistent practice across NICUs. A modified Finnegan scoring tool was used for both preterm and term infants. Morphine was reported as the most common first-line drug used for treatment. IMPLICATIONS FOR PRACTICE: Great variability in NAS practice for preterm infants born at less than 34 weeks of gestational age across the multiple NICUs supports the need for a validated preterm infant assessment tool and development of appropriate treatment strategies. IMPLICATIONS FOR RESEARCH: Future research describing the NAS symptomatology of preterm infants born at less than 34 weeks of gestational age exposed to intrauterine opioids is warranted.

A global point prevalence survey of antimicrobial use in neonatal intensive care units: The no-more-antibiotics and resistance (NO-MAS-R) study.

BACKGROUND: Global assessment of antimicrobial agents prescribed to infants in the neonatal intensive care unit (NICU) may inform antimicrobial stewardship efforts. METHODS: We conducted a one-day global point prevalence study of all antimicrobials provided to NICU infants. Demographic, clinical, and microbiologic data were obtained including NICU level, census, birth weight, gestational/chronologic age, diagnoses, antimicrobial therapy (reason for use; length of therapy), antimicrobial stewardship program (ASP), and 30-day in-hospital mortality. FINDINGS: On July 1, 2019, 26% of infants (580/2,265; range, 0-100%; median gestational age, 33 weeks; median birth weight, 1800 g) in 84 NICUs (51, high-income; 33, low-to-middle income) from 29 countries (14, high-income; 15, low-to-middle income) in five continents received ≥1 antimicrobial agent (92%, antibacterial; 19%, antifungal; 4%, antiviral). The most common reasons for antibiotic therapy were "rule-out" sepsis (32%) and "culture-negative" sepsis (16%) with ampicillin (40%), gentamicin (35%), amikacin (19%), vancomycin (15%), and meropenem (9%) used most frequently. For definitive treatment of presumed/confirmed infection, vancomycin (26%), amikacin (20%), and meropenem (16%) were the most prescribed agents. Length of therapy for culture-positive and "culture-negative" infections was 12 days (median; IQR, 8-14) and 7 days (median; IQR, 5-10), respectively. Mortality was 6% (42%, infection-related). An NICU ASP was associated with lower rate of antibiotic utilization (p = 0·02). INTERPRETATION: Global NICU antibiotic use was frequent and prolonged regardless of culture results. NICU-specific ASPs were associated with lower antibiotic utilization rates, suggesting the need for their implementation worldwide. FUNDING: Merck & Co.; The Ohio State University College of Medicine Barnes Medical Student Research Scholarship.

Evaluation of the Efficacy of Enoxaparin in the Neonatal Intensive Care Unit.

OBJECTIVE: This article evaluates the efficacy of enoxaparin when targeting anti-factor Xa levels of 0.5 to 1 units per milliliter in the neonatal intensive care unit. STUDY DESIGN: This is a retrospective chart review of 45 neonates receiving enoxaparin for the treatment of venous thromboembolism. Enoxaparin dosing and corresponding anti-factor Xa levels were collected. Time to resolution of clot was confirmed by imaging and compared between clots in various locations. RESULTS: The median time to clot resolution was 76 days (interquartile range 40-91 days). Clot location, postnatal age, and sex at the clot onset were significantly associated with time to clot resolution in a multivariable Cox model (p-value: 0.03, 0.03, and < 0.01, respectively). Of the 54 patients analyzed for safety, 5 patients (9.3%) experienced bleeding events resulting in the discontinuation of enoxaparin. CONCLUSION: Based on our findings, 50% of all patients evaluated, regardless of thrombus location, achieved resolution within the first 76 days of therapy. Clots located in the extremities tended to resolve sooner, hence earlier reimaging should be considered.

Parenteral Nutrition in Moderately Preterm, Otherwise Healthy Neonates Is Not Associated With Improved Short-Term Growth Outcomes.

BACKGROUND: Parenteral nutrition (PN) serves a crucial role in providing nutrition to extremely premature infants who are at high risk for malnutrition. However, little is known about the impact of PN on short-term growth outcomes in moderately preterm infants. METHODS: In this retrospective cohort analysis, patients were included in the study if they were born at ≥32 but <34 weeks gestational age and had no major comorbidities. The primary outcome of this study was to determine whether initiation of early PN for these patients has any effect on daily weight gain compared with standard dextrose-containing fluids (DCFs). Secondary outcomes were to evaluate the differences in time to regain birth weight, length of stay, and change in weight, length, and head circumference percentiles from birth to discharge. Incidence of necrotizing enterocolitis, antibiotic usage, or supplemental oxygen utilization was also evaluated. RESULTS: There were 89 patients in the PN group and 35 patients in the DCF group. The mean daily weight gain was not different between PN and DCF groups when calculated from birth to discharge (11.8 vs 10 g/kg/d, respectively; P = .09). There were also no differences when weight gain was calculated from nadir to discharge: 16.8 vs 15.2 g/kg/d, respectively (P = .1). Lack of differences persisted even when propensity matching was performed. CONCLUSION: Based on the study findings, neonates born ≥32 weeks of gestational age without any major comorbidities are unlikely to benefit from PN supplementation.

Clinical Decision Support to Improve Dosing Weight Use in Infants with Neonatal Abstinence Syndrome.

INTRODUCTION: Opioid abuse in the United States is a public health emergency. From 2000 to 2009, prenatal maternal opiate use increased from 1.19 to 5.63 per 1,000 births, with up to 80% of in utero opioid-exposed infants requiring pharmacotherapy. This study aimed to increase the percentage of neonatal abstinence syndrome (NAS) medication orders based on birth weight (BW) in neonates admitted to a neonatal intensive care unit with a principal diagnosis of NAS from 29% to 90%, within 4 months of project initiation, and to sustain this for 6 months. METHODS: This project occurred at an academic medical center with 5,000 deliveries per year and a 49-bed Level III neonatal intensive care unit. We used the Institute for Healthcare Improvement methodology, largely focusing interventions on clinical decision support (CDS) tools. We plotted all measures on Shewhart charts, and Nelson rules differentiated special versus common cause variation. RESULTS: The percent of orders based on BW increased from 29% to 78% after implementing multiple interventions focused primarily on CDS. However, this later decreased to 48% as workarounds began. There was also a significant decrease in the length of stay variability, which persisted throughout the project. DISCUSSION: CDS is a helpful tool to guide prescribing behavior; however, workarounds can negate its usefulness. Standardized use of BW for weight-based NAS medication prescribing can decrease the length of stay variability. Further studies are needed using a human factors approach to minimize workarounds in CDS and potentially decrease the length of stay in neonates with NAS.

Acetaminophen and Acetylsalicylic Acid Exposure in a Preterm Infant after Maternal Overdose.

Here, we review the case of a 26 1/7 weeks' gestation premature female infant born to a mother who intentionally ingested a large quantity of Tylenol, aspirin, quetiapine, and prenatal vitamins. The neonate subsequently had markedly elevated levels of both Tylenol and aspirin when checked on the first day of life. While overall clinically stable, the neonate did demonstrate coagulopathy as evidenced by abnormal coagulation studies. Both poison control and a pediatric gastroenterologist/hepatologist were consulted. She successfully tolerated a course of N-acetylcysteine; her subsequent Tylenol level was markedly decreased and the neonate exhibited no further effects of toxicity. The salicylate level decreased on its own accord. To our knowledge, this is the first report of a neonate at 26 weeks' gestation that has been successfully managed for supratherapeutic concentrations of acetaminophen and acetylsalicylic acid secondary to maternal ingestion. While rare, this case may serve as a reference for the effectiveness of N-acetylcysteine in premature infants in such instances.

In vivo imaging of atherosclerotic plaques in apolipoprotein E deficient mice using nonlinear microscopy.

Structural proteins such as elastin and collagen can be readily imaged by using two-photon excitation and second-harmonic generation microscopic techniques, respectively, without physical or biochemical processing of the tissues. This time- and effort-saving advantage makes these imaging techniques convenient for determining the structural characteristics of blood vessels in vivo. Fibrillar collagen is a well-known element involved in the formation of atherosclerotic lesions. It is also an important component of the fibrous cap responsible for structural stability of atherosclerotic plaques. High resolution in vivo microscopic imaging and characterization of atherosclerotic lesions in animal models can be particularly useful for drug discovery. However, it is hindered by the limitations of regular microscope objectives to gain access of the tissues of interest and motional artifacts. We report a technique that facilitates in vivo microscopic imaging of carotid arteries of rodents using conventional microscope objectives, and at the same time avoids motional artifacts. As a result, collagen, elastin, leukocytes, cell nuclei, and neutral lipids can be visualized in three dimensions in live animals. We present and discuss in vivo imaging results using a flow cessation mouse model of accelerated atherosclerosis.