3D-Printed Enzyme-Embedded Plastics.

A simple and environmentally friendly approach toward the thermoplastic processing of rapidly degradable plastic-enzyme composites using three-dimensional (3D) printing techniques is described. Polycaprolactone/Amano lipase (PCL/AL) composite films (10 mm × 10 mm; height [h] = ∼400 µm) with an AL loading of 0.1, 1.0, and 5.0% were prepared via 3D printing techniques that entail direct mixing in the solid state and thermal layer-by-layer extrusion. It was found that AL can tolerate in situ processing temperatures up to 130 °C in the solid-state for 60 min without loss of enzymatic activity. The composites were degraded in phosphate buffer (8 mg/mL, composite to buffer) for 7 days at 37 °C and the resulting average percent total weight loss (WLavg %) was found to be 5.2, 92.9, and 100%, for the 0.1, 1.0, and 5.0% films, respectively. The degradation rates of PCL/AL composites were found to be faster than AL applied externally in the buffer. Thicker PCL/AL 1.0% films (10 mm × 10 mm; h = ∼500 µm) were also degraded over a 7 day period to examine how the weight loss occurs over time with 3.0, 18.1, 36.4, 46.4, and 70.2% weight loss for days 1, 2, 3, 4, and 7, respectively. Differential scanning calorimetry (DSC) analysis shows that the film's percent crystallinity (Dxtal%) increases over time with Dxtal% = 46.5 for day 0 and 53.1% for day 7. Scanning electron microscopy (SEM) analysis found that film erosion begins at the surface and that water can penetrate the interior via surface pores activating the enzymes embedded in the film. Controlled release experiments utilizing dye-loaded PCL/AL/dye (AL = 1.0%; dye = 0.1%) composites were degraded over a 7 day period with the bulk of the dye released by the fourth day. The PCL/AL multimaterial objects containing AL-resistant polylactic acid (PLA) were also printed and degraded to demonstrate the application of this material on more complex structures.

Dosing and Safety of Off-label Use of Caffeine Citrate in Premature Infants.

OBJECTIVE: To characterize the dosing and safety of off-label caffeine citrate in a contemporary cohort of extremely premature infants. STUDY DESIGN: We used electronic health records (2010-2013) from 4 neonatal intensive care units to identify infants of ≤28 weeks of gestational age exposed to caffeine citrate. Safety outcomes included death, bronchopulmonary dysplasia, necrotizing enterocolitis, spontaneous intestinal perforation, intraventricular hemorrhage, patent ductus arteriosus ligation, seizures, and arrhythmias. We used multivariable logistic regression to evaluate the association of caffeine citrate exposure with clinical events. RESULTS: Of 410 infants with a median (IQR) gestational age of 26 (24-27) weeks, 95% received caffeine citrate for >0 days. Infants received a median (IQR) daily dose of 8 (5-10) mg/kg/day. Incidences of clinical events on day of caffeine citrate exposure were death 2%, patent ductus arteriosus ligation 12%, and medical and surgical necrotizing enterocolitis 5% and 4%, respectively. Bronchopulmonary dysplasia occurred in 37% of infants and was not associated with caffeine dose. Increased caffeine citrate dose was associated with lower odds of patent ductus arteriosus ligation and necrotizing enterocolitis. CONCLUSIONS: Caffeine citrate was used in extremely premature infants at younger gestation, at higher doses, and for longer durations than recommended on the drug label. Increased caffeine citrate exposure, dose, or therapy duration was not associated with increased risk of necrotizing enterocolitis.

The Mechanical Role of the Radial Fiber Network Within the Annulus Fibrosus of the Lumbar Intervertebral Disc: A Finite Elements Study.

The annulus fibrosus (AF) of the intervertebral disc (IVD) consists of a set of concentric layers composed of a primary circumferential collagen fibers arranged in an alternating oblique orientation. Moreover, there exists an additional secondary set of radial translamellar collagen fibers which connects the concentric layers, creating an interconnected fiber network. The aim of this study was to investigate the mechanical role of the radial fiber network. Toward that goal, a three-dimensional (3D) finite element model of the L3-L4 spinal segment was generated and calibrated to axial compression and pure moment loading. The AF model explicitly recognizes the two heterogeneous networks of fibers. The presence of radial fibers demonstrated a pronounced effect on the local disc responses under lateral bending, flexion, and extension modes. In these modes, the radial fibers were in a tensile state in the disc region that subjected to compression. In addition, the circumferential fibers, on the opposite side of the IVD, were also under tension. The local stress in the matrix was decreased in up to 9% in the radial fibers presence. This implies an active fiber network acting collectively to reduce the stresses and strains in the AF lamellae. Moreover, a reduction of 26.6% in the matrix sideways expansion was seen in the presence of the radial fibers near the neutral bending axis of the disc. The proposed biomechanical model provided a new insight into the mechanical role of the radial collagen fibers in the AF structure. This model can assist in the design of future IVD substitutes.

GEORG SCHMORL PRIZE OF THE GERMAN SPINE SOCIETY (DWG) 2018: combined inflammatory and mechanical stress weakens the annulus fibrosus: evidences from a loaded bovine AF organ culture.

PURPOSE: The pathomechanism of annulus fibrosus (AF) failure is still unknown. We hypothesise that mechanical overload and an inflammatory microenvironment contribute to AF structural weakening. Therefore, the objective of this study was to investigate the influence of these factors on the AF, particularly the translamellar bridging network (TLBN) which connects the AF lamellae. METHODS: A bovine AF organ culture (AF-OC) model of standardised AF rings was used to study the individual and combined effects of cyclic tensile strain (CTS) and IL-1ß (1 ng/mL) culture medium supplementation. AF-OCs were analysed for PGE2 production (ELISA) and deposition of IL-6, COX-2, fibrillin, and MMP3 in the tissue (immunohistochemistry, IHC). The mechanical strength of the TLBN was evaluated using a peel test to measure the strength required to separate an AF segment along a lamellar bound. RESULTS: The combination of CTS + IL-1ß led to a significant increase in PGE2 production compared to Control (p < 0.01). IHC evaluations showed that the CTS + IL-1ß group exhibited higher production of COX-2 and MMP3 within the TLBN regions compared to the adjacent lamellae and a significant increase in IL-6 ratio compared to Control (p < 0.05). A significant decrease in the annular peel strength was observed in the CTS + IL1ß group compared to Control (p < 0.05). CONCLUSION: Our findings suggest that CTS and IL-1ß act synergistically to increase pro-inflammatory and catabolic molecules within the AF, particularly the TLBN, leading to a weakening of the tissue. This standardised model enables the investigation of AF/TLBN structure-function relationship and is a platform to test AF-focused therapeutics. These slides can be retrieved under Electronic Supplementary Material.

Measles Serostatus Among Parturient Patients at 2 Philadelphia Hospitals in 2021.

This observational study explores whether rubella serostatus, which is routinely assessed during pregnancy, can serve as a proxy for measles serostatus in parturient persons.

External Evaluation of Two Fluconazole Infant Population Pharmacokinetic Models.

Fluconazole is an antifungal agent used for the treatment of invasive candidiasis, a leading cause of morbidity and mortality in premature infants. Population pharmacokinetic (PK) models of fluconazole in infants have been previously published by Wade et al. (Antimicrob Agents Chemother 52:4043-4049, 2008, https://doi.org/10.1128/AAC.00569-08) and Momper et al. (Antimicrob Agents Chemother 60:5539-5545, 2016, https://doi.org/10.1128/AAC.00963-16). Here we report the results of the first external evaluation of the predictive performance of both models. We used patient-level data from both studies to externally evaluate both PK models. The predictive performance of each model was evaluated using the model prediction error (PE), mean prediction error (MPE), mean absolute prediction error (MAPE), prediction-corrected visual predictive check (pcVPC), and normalized prediction distribution errors (NPDE). The values of the parameters of each model were reestimated using both the external and merged data sets. When evaluated with the external data set, the model proposed by Wade et al. showed lower median PE, MPE, and MAPE (0.429 µg/ml, 41.9%, and 57.6%, respectively) than the model proposed by Momper et al. (2.45 µg/ml, 188%, and 195%, respectively). The values of the majority of reestimated parameters were within 20% of their respective original parameter values for all model evaluations. Our analysis determined that though both models are robust, the model proposed by Wade et al. had greater accuracy and precision than the model proposed by Momper et al., likely because it was derived from a patient population with a wider age range. This study highlights the importance of the external evaluation of infant population PK models.

A more realistic disc herniation model incorporating compression, flexion and facet-constrained shear: a mechanical and microstructural analysis. Part I: Low rate loading.

PURPOSE: To date, the mechanisms of disc failure have been explored at a microstructural level in relatively simple postures. However, in vivo the disc is known to be subjected to complex loading in compression, bending and shear, and the influence of these factors on the mechanisms of disc failure is yet to be described at a microstructural level. The purpose of this study was to provide a microstructural analysis of the mechanisms of failure in healthy discs subjected to compression while held in a complex posture incorporating physiological amounts of flexion and facet-constrained shear. METHODS: 30 motion segments from 10 healthy mature ovine lumbar spines were compressed in a complex posture intended to simulate the situation arising when bending and twisting while lifting a heavy object, and at a displacement rate of 40 mm/min. Nine of the 30 samples reached the predetermined displacement prior to a reduction in load and were classified as early-stage failures, providing insight into initial areas of disc disruption. Both groups of damaged discs were then analysed microstructurally using light microscopy. RESULTS: Complex postures significantly reduced the load required to cause disc failure than earlier described for flexed postures [8.42 kN (STD 1.22 kN) compared to 9.69 kN (STD 2.56 kN)] and resulted in a very different failure morphology to that observed in either simple flexion or direct compression, involving infiltration of nucleus material in a circuitous path to the annular periphery. CONCLUSION: The complex posture as used in this study significantly reduced the load required to cause disc failure, providing further evidence that asymmetric postures while lifting should be avoided if possible.

Staying connected: structural integration at the intervertebral disc-vertebra interface of human lumbar spines.

PURPOSE: To investigate the microscopic fibrous integration between the intervertebral disc, cartilage endplates and vertebral endplates in human lumbar spines of varying degrees of degeneration using differential interference contrast (DIC) optics. Weakness at these junctions is considered to be an important factor in the aetiology of disc herniations. METHODS: Magnetic resonance images (MRIs) of cadaveric lumbar spines were graded for degeneration and motion segments from a range of degenerative grades isolated and bisected sagittally. Following fixation and decalcification, these were cut into segments containing anterior or posterior annulus fibrosus or nucleus pulposus. The segments were cryo-sectioned and sections visualised using both standard light and DIC microscopy. RESULTS: Detachment at the interface between the disc and vertebrae increased with greater degenerative grade (from 1.9 % in Grade I to 28 % in Grade V), especially at the boundary between the cartilage and vertebral endplates. DIC microscopy revealed the fibrous organisation at the IVD-cartilage endplate interface with structural features, such as annular lamellae branching and nodal insertions in the nucleus pulposus region; these have been previously observed in ovine spines, but were less uniform in humans. Structural integrity of the IVD and cartilage endplate was also lost with increasing degeneration. CONCLUSIONS: This preliminary study shows that microscopic structural features may act to maintain attachment between the IVD and CEP in the human spine. Loss of structural integrity in this region may destabilise the spine, possibly altering the mechanical environment of the cells in the disc and so potentially contribute to the aetiopathogenesis of IVD degeneration.

A more realistic disc herniation model incorporating compression, flexion and facet-constrained shear: a mechanical and microstructural analysis. Part II: high rate or 'surprise' loading.

PURPOSE: Part I of this study explored mechanisms of disc failure in a complex posture incorporating physiological amounts of flexion and shear at a loading rate considerably lower than likely to occur in a typical in vivo manual handling situation. Given the strain-rate-dependent mechanical properties of the heavily hydrated disc, loading rate will likely influence the mechanisms of disc failure. Part II investigates the mechanisms of failure in healthy discs subjected to surprise-rate compression while held in the same complex posture. METHODS: 37 motion segments from 13 healthy mature ovine lumbar spines were compressed in a complex posture intended to simulate the situation arising when bending and twisting while lifting a heavy object at a displacement rate of 400 mm/min. Seven of the 37 samples reached the predetermined displacement prior to a reduction in load and were classified as early stage failures, providing insight to initial areas of disc disruption. Both groups of damaged discs were then analysed microstructurally using light microscopy. RESULTS: The average failure load under high rate complex loading was 6.96 kN (STD 1.48 kN), significantly lower statistically than for low rate complex loading [8.42 kN (STD 1.22 kN)]. Also, unlike simple flexion or low rate complex loading, direct radial ruptures and non-continuous mid-wall tearing in the posterior and posterolateral regions were commonly accompanied by disruption extending to the lateral and anterior disc. CONCLUSION: This study has again shown that multiple modes of damage are common when compressing a segment in a complex posture, and the load bearing ability, already less than in a neutral or flexed posture, is further compromised with high rate complex loading.

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams.

Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.

Changes in Course of Retinopathy of Prematurity from 1986 to 2013: Comparison of Three Studies in the United States.

PURPOSE: To compare infant and retinopathy of prematurity (ROP) characteristics from 3 clinical studies conducted over a 27-year period in the United States. DESIGN: Secondary analysis of results of 3 clinical studies. PARTICIPANTS: Infants with birth weight (BW) <1251 g. METHODS: Analysis of data from the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) and Early Treatment for Retinopathy of Prematurity (ETROP) trials and the primary data from the Telemedicine Approaches for the Evaluation of Acute-Phase Retinopathy of Prematurity (e-ROP) study. MAIN OUTCOME MEASURES: Infant characteristics and onset, severity, and time course of ROP. RESULTS: Across the 3 studies, mean (standard deviation) BW and mean gestational age (GA) decreased over time from CRYO-ROP (954 g [185 g], 27.9 weeks [2.2 weeks]) to ETROP (907 g [205 g], 27.4 weeks [2.2 weeks]) to e-ROP (864 g [212 g], 27.0 weeks [2.2 weeks]), with an increase in the percentage of infants enrolled weighing <750 g (15.8% CRYO, 24.9% ETROP, 33.4% e-ROP; P<0.0001). The percentage of infants who developed ROP varied only minimally (65.8% CRYO, 68.0% ETROP, 63.7% e-ROP; P = 0.003). Moderately severe ROP (defined as prethreshold or referral warranted) varied (17.8% CRYO, 12.3% ETROP, 19.4% e-ROP; P<0.0001), whereas the time of onset of any ROP did not vary (34.3 weeks CRYO, 34.1 weeks ETROP, 34.8 weeks e-ROP). CONCLUSIONS: The BW and GA of infants enrolled in ROP studies in the United States have decreased over the past 27 years, whereas ROP prevalence and onset of disease are stable.

Adverse Events in Young and Preterm Infants Receiving Topical Timolol for Infantile Hemangioma.

BACKGROUND: The success of oral propranolol for treatment of infantile hemangiomas (IHs) has led practitioners to use topical ß-blockers. In preterm infants, clinicians frequently turn to topical timolol, with the presumption that topical application will result in less systemic absorption. We used Holter monitoring to assess for drug-induced bradycardia in high-risk infants. METHODS: We retrospectively reviewed the charts of 22 at-risk infants who received a Holter monitor to assess for association between timolol administration and development of significant bradycardia. RESULTS: Four infants had episodic bradycardia detected by Holter monitoring. Two of these infants were full term; weighed more than 3,000 g; and had rare, brief, asymptomatic episodes unrelated to the timing of the timolol application. The other two infants had symptomatic bradycardia while on timolol and were the only two babies that weighed less than 2,500 g at initiation of therapy. Both were young (postmenstrual age [PMA] 34 and 37 wks) at initiation and had a timolol dose above the average exposure for the cohort. CONCLUSION: In this cohort of at-risk infants, topical timolol appeared to provide safe treatment for IHs in full-term infants receiving a dose of less than 0.2 mg/kg/day, but infants with a PMA of less than 44 weeks and weight at treatment initiation of less than 2,500 g may be at risk of adverse events, including bradycardia, hypotension, apnea, and hypothermia. We recommend close monitoring of temperature, blood pressure, and heart rate in premature and low-birthweight infants with IHs at initiation of and during therapy with topical timolol.

Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation.

Candida infections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. The PK data were analyzed using nonlinear mixed-effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution (V). The final model included the effect of serum creatinine (SCR) level on CL and the effect of ECMO on V as follows: CL (in liters per hour) = 0.019 × weight × (SCR/0.4)(-0.29) × exp(ηCL) and V (in liters) = 0.93 × weight × 1.4(ECMO) × exp(ηV). The fluconazole V was increased in children supported by ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12 mg/kg of body weight) and treatment (35 mg/kg) paired with standard maintenance doses to achieve exposures similar to those of children not on ECMO.

Retinopathy of prematurity risk prediction for infants with birth weight less than 1251 grams.

OBJECTIVE: To predict retinopathy of prematurity (ROP) exam findings among infants with birth weight <1251 g from 32-40 weeks postmenstrual age (PMA). STUDY DESIGN: Secondary analysis of 3714 eye exams from 1239 infants. RESULTS: The likelihood of developing type 1 ROP by 40 weeks PMA varied by gestational age (GA) (P < .001), from 33% for ≤25 weeks, 10% for 26 or 27 weeks, 4% for 28 or 29 weeks, and none for ≥30 weeks. By 40 weeks PMA, 51% with GA ≤27 weeks still needed subsequent exams. Previous exam findings, GA, and PMA were predictive of the development of type 1 ROP (area under the curve, 0.78) or mature retina (area under the curve, 0.85). CONCLUSIONS: This analysis provides the opportunity for development of an ROP approach to estimate resource needs in the neonatal intensive care unit and to facilitate communication with families when planning discharge or transfer.

Safety of Retinopathy of Prematurity Examination and Imaging in Premature Infants.

OBJECTIVES: To describe adverse events (AEs) and noteworthy clinical or ocular findings associated with retinopathy of prematurity (ROP) evaluation procedures. STUDY DESIGN: Descriptive analysis of predefined AEs and noteworthy findings reported in a prospective observational cohort study of infants <1251 g birth weight who had ROP study visits consisting of both binocular indirect ophthalmoscopy (BIO) and digital retinal imaging. We compared infant characteristics during ROP visits with and without AEs. We compared respiratory support, nutrition, and number of apnea, bradycardia, or hypoxia events 12 hours before and after ROP visits. RESULTS: A total of 1257 infants, mean birth weight 802 g, had 4263 BIO and 4048 imaging sessions (total 8311 procedures). No serious AEs were related to ROP visits. Sixty-five AEs were reported among 61 infants for an AE rate of 4.9% infants (61/1257) or 0.8% total procedures (65/8311 BIO + imaging). Most AEs were due to apnea, bradycardia, and/or hypoxia (68%), tachycardia (16%), or emesis (8%). At ROP visit, infants with AEs, compared with those without, were more likely to be on mechanical ventilation (26% vs 12%, P = .04) even after adjustment for weight and postmenstrual age. Noteworthy clinical findings were reported during 8% BIO and 15% imaging examinations. Respiratory and nutrition support were not significantly different before and after ROP evaluations. CONCLUSIONS: Retinal imaging by nonphysicians combined with BIO was safe. Noteworthy clinical findings occurred during both procedures. Ventilator support was a risk factor for AEs. Monitoring rates of AEs and noteworthy findings are important to the safe implementation of ROP imaging protocols. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01264276.

Influence of maturity on nucleus-endplate integration in the ovine lumbar spine.

PURPOSE: Recent investigations using an ovine spine model have established that the disc nucleus contains a highly convoluted fibre network with endplate-to-endplate connectivity, this connectivity being achieved via distinctive nodal attachment points. The purpose of this study was to investigate how this nodal anchoring system might be influenced by maturation. METHODS: Lumbar motion segments were dissected from newborn, 3, 12 months and fully mature ovine animals, subjected to a novel annular ring-severing procedure to remove the strain-limiting influence of the annulus, then either mechanically tested to destruction or examined microstructurally and ultrastructurally. The morphology of the nodes and their linear density within the relatively thin section planes were analysed to provide a basis for comparison between the four age groups. RESULTS: Mechanical testing following ring severing revealed that the remaining nuclear material in all samples, irrespective of maturity, had the ability to transmit a substantial load from endplate to endplate. Imaging of the ring-severed samples from all age groups in their stretched, but unruptured state revealed the presence of axially aligned fibrosity in the nucleus region consistent with endplate-to-endplate connectivity. Endplate insertion nodes were observed in all age groups. Ultrastructural examination revealed that the fibrillar architecture of these nodes in the newborn discs was similar to that observed in the nodes of mature discs. However, there was a rapid increase in their linear density between birth and 3 months, after which this remained constant. CONCLUSIONS: The nodal attachment points identified previously in mature ovine discs are also present in newborn, and 3- and 12-month-old animals with an initial rapid increase in their linear density between birth and 3 months, after which it remained constant. The size and morphology of the attachment points were similar for all ages. Our study suggests that the increase in nodal density in the ovine disc endplate is part of an adaptive response to the loading environment that the disc is exposed to from birth to maturity.

Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial.

IMPORTANCE: Invasive candidiasis in premature infants causes death and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole are unknown. OBJECTIVE: To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants. DESIGN, SETTING, AND PATIENTS: This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013. INTERVENTIONS: Fluconazole (6 mg/kg of body weight) or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes-defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18 to 22 months corrected age. RESULTS: Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%-22%) vs 21% in the placebo group (95% CI, 15%-28%; odds ratio, 0.73 [95% CI, 0.43-1.23]; P = .24; treatment difference, -5% [95% CI, -13% to 3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%-6%]) vs the placebo group (9% [95% CI, 5%-14%]; P = .02; treatment difference, -6% [95% CI, -11% to -1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole, 31% [95% CI, 21%-41%] vs placebo, 27% [95% CI, 18%-37%]; P = .60; treatment difference, 4% [95% CI, -10% to 17%]). CONCLUSIONS AND RELEVANCE: Among infants with a birth weight of less than 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00734539.

Antibiotic use among extremely low birth-weight infants from 2009 to 2021: a retrospective observational study.

OBJECTIVE: To assess trends in antibiotic use across a large cohort of extremely low birth-weight (<1000 g; ELBW) infants admitted to academic and community neonatal intensive care units (NICUs) across the USA over a 13-year period. DESIGN: Repeated cross-sectional cohort study. SETTING: Premier Health Database, a comprehensive administrative database of inpatient encounters from academic and community hospitals across the US. PATIENTS: ELBW inborn infants admitted to NICUs from 1 January 2009 to 31 December 2021. INTERVENTIONS: N/A MAIN OUTCOME MEASURES: Absolute and relative changes in (1) proportion of ELBW infants with antibiotic exposure and (2) days of therapy (DOT) per 1000 patient days, over time. Average annual differences were estimated using generalised linear regression with 95% CI. Disposition trends were also measured. RESULTS: Among 36 701 infants admitted to 402 NICUs, the proportion exposed to antibiotics was essentially unchanged (89.9% in 2009 to 89.3% in 2021; absolute reduction of -0.6%); generalised linear regression estimated an annual absolute difference of -0.3% (95% CI (-0.6%) to (-0.07%); p=0.01). DOT per 1000 patient days decreased from 337 in 2009 to 210 in 2021, a 37.8% relative difference and annual relative difference of -4.3% ((-5.2%) to (-3.5%); p<0.001). Mortality was unchanged during the study period. CONCLUSIONS: We found a substantial reduction in antibiotic DOT despite no substantive change in the proportion of infants exposed to antibiotics. This suggests the success of stewardship efforts aimed at antibiotic duration and highlight the need for improved approaches to identifying ELBW infants at highest risk of infection.

Postdiscontinuation Antibiotic Exposure in Hospitalized Infants at Risk for Late-onset Sepsis in the Neonatal Intensive Care Unit.

BACKGROUND: In the neonatal intensive care unit, infants are at risk for late-onset sepsis. When blood cultures are negative, antibiotic stewardship efforts encourage stopping antibiotics, yet the duration of therapeutic exposure after the last dose is unknown. METHODS: This retrospective cohort study of simulated antibiotic exposures used published population pharmacokinetic models within drug-specific neonatal intensive care unit cohorts of preterm and term infants, postnatal age 7-60 days and exposed to cefepime, piperacillin-tazobactam or tobramycin. Monte Carlo simulations (NONMEM 7.3) were used to predict steady-state exposures after a 72-hour antibiotic course per Neofax dosing. Exposure was assessed relative to drug-specific minimum inhibitory concentration (MIC) targets between 1 and 16 mcg/mL for Pseudomonas and Enterobacteriaceae species. Postdiscontinuation antibiotic exposure (PDAE) was defined as the time from the last dose to when antibiotic concentration decreased below a specific MIC. RESULTS: Piperacillin-tazobactam, cefepime and tobramycin cohorts included infants with median gestation age 29, 32 and 32 weeks and postnatal age 17, 19 and 15 days, respectively. The mean PDAE was 19-68 hours, depending on the specific antibiotic/MIC combination. PDAE was longer for infants <28 days old and preterm (vs. term) infants. Cefepime exhibited the longest mean PDAE of 68 hours for Enterobacteriaceae MIC 1. Piperacillin mean PDAE was 25 hours for Enterobacteriaceae MIC 8. Tobramycin had a short mean PDAE of 19 hours. CONCLUSIONS: Piperacillin and cefepime exposures remained therapeutic long after the expected 8- to 12-hour dosing interval. PDAE is an important consideration for antibiotic stewardship among hospitalized infants, particularly premature infants and those within 1 month postbirth.