Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries.

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

Comparison of Growth Outcomes Between Human Milk-Fed Preterm Infants on Standard Versus Adjustable Fortification Protocols.

Background: Human milk (HM) is usually fortified using standard fortification (STD) to improve nutrition of preterm infants. However, the protein component may still be insufficient. HM could be further fortified with additional protein to improve STD. Objective: The primary objective was to compare changes in body weight (g/day, g/kg/day), length, and head circumference (mm/day) between preterm neonates fed HM with STD and those fed HM with adjustable fortification (ADJ). Methods: This study was a prospective, single-blinded, randomized controlled study in preterm infants of gestational age <32 weeks and weighing ≤1,800 g, admitted to the neonatal unit of the Queen Sirikit National Institute of Child Health. Once the infants received full HM feed with STD at 24 kcal/oz, they were randomized to either continue with STD or with ADJ group by adding additional protein to the STD and making further protein adjustments based on the blood urea nitrogen levels. Results: Thirty preterm infants completed the study and were randomized into two groups of 15 each. The baseline characteristics, total fluid, and energy intake were similar. Compared with the STD group, infants in the ADJ group exhibited significantly greater weight gain (36.46 ± 6.09 vs. 25.78 ± 8.81 g/day; p = 0.001) and greater length gain (1.93 ± 0.57 vs. 1.12 ± 0.64 mm/day; p = 0.001). Protein intake significantly correlated with both weight (r = 0.632, p < 0.001) and length gain (r = 0.577, p = 0.001); however, no correlation was found between energy intake, volume intake, and growth outcomes. Conclusion: Preterm infants fed with ADJ had significantly higher weight and length gains than those fed with STD, suggesting that additional protein intake may play an important role in growth.

Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS).

BACKGROUND: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. METHODS AND FINDINGS: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. CONCLUSION: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03721302).

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Efficacy comparison between oral erythromycin versus domperidone for the treatment of feeding intolerance in preterm neonates.

BACKGROUND: Domperidone and erythromycin are commonly used as prokinetic agents for feeding intolerance in preterm neonates; however, no data from a previous study have compared their efficacy. This study aimed to compare the efficacy of orally administered domperidone and erythromycin for the treatment of feeding intolerance in preterm infants. METHODS: This retrospective cohort study included preterm neonates with a birthweight of <1800 g and gestational age <37 weeks. Data were collected from medical records at Queen Sirikit National Institute of Child Health (QSNICH) from 2006 to 2014. The primary outcome was the time to establish full enteral feeding (150 ml/kg/day) after starting oral domperidone or erythromycin for the treatment of feeding intolerance in preterm neonates. The secondary outcome was adverse effects associated with domperidone and erythromycin therapy. RESULTS: Among the 150 preterm neonates enrolled in this study, 66 received domperidone, and 84 received erythromycin. The baseline characteristics and comorbidities were not significantly different between the two groups; however, the gestational age at birth of neonates in the domperidone group was significantly lower than that of those in the erythromycin group. The time to establish full enteral feeding did not differ between the domperidone (11 days, "IQR," [6, 17]) and erythromycin (10 days, IQR [7, 14]) groups (p = 0.622). No major adverse effects were noted. There were only three preterm infants who had elevated liver enzymes in each group, but the difference between groups was not significant. CONCLUSION: From this study, the efficacy of oral domperidone was promising equivalent to oral erythromycin and seems to be one of the treatment options for feeding intolerance in preterm neonates. However, large randomized, controlled trials are needed to confirm the efficacy and safety of domperidone in this population.

Fetal skin as a pro-inflammatory organ: Evidence from a primate model of chorioamnionitis.

BACKGROUND: Intrauterine infection is a primary cause of preterm birth and fetal injury. The pro-inflammatory role of the fetal skin in the setting of intrauterine infection remains poorly characterized. Whether or not inflammation of the fetal skin occurs in primates remains unstudied. Accordingly, we hypothesized that: i) the fetal primate skin would mount a pro-inflammatory response to preterm birth associated pro-inflammatory agents (lipopolysaccharides from Escherichia coli, live Ureaplasma parvum, interleukin-1ß) and; ii) that inhibiting interleukin-1 signaling would decrease the skin inflammatory response. METHODS: Rhesus macaques with singleton pregnancies received intraamniotic injections of either sterile saline (control) or one of three pro-inflammatory agonists: E. coli lipopolysaccharides, interluekin-1ß or live U. parvum under ultrasound guidance. A fourth group of animals received both E. coli lipopolysaccharide and interleukin-1 signaling inhibitor interleukin-1 receptor antagonist (Anakinra) prior to delivery. Animals were surgically delivered at approximately 130 days' gestational age. RESULTS: Intraamniotic lipopolysaccharide caused an inflammatory skin response characterized by increases in interluekin-1ß,-6 and -8 mRNA at 16 hours. There was a modest inflammatory response to U. parvum, but interleukin-1ß alone caused no inflammatory response in the fetal skin. Intraamniotic Anakinra treatment of lipopolysaccharide-exposed animals significantly reduced skin inflammation. CONCLUSIONS: Intraamniotic lipopolysaccharide and U. parvum were associated with modest increases in the expression of inflammatory mediators in primate fetal skin. Although administration of Interleukin-1ß alone did not elicit an inflammatory response, lipopolysaccharide-driven skin inflammation was decreased following intraamniotic Anakinra therapy. These findings provide support for the role of the fetal skin in the development of the fetal inflammatory response.

An optimal cut-off point of serum C-reactive protein in prediction of neonatal sepsis.

OBJECTIVE: To determine an optimal cut-off point of serum C-reactive protein (CRP) levels for prediction of neonatal sepsis. MATERIAL AND METHOD: A prospective cohort study of neonates aged from birth to 30 days old presenting with signs and symptoms of neonatal sepsis in neonatal intensive care unit (NICU) from January 2010 through December 2011 was performed. Neonates were assigned to either sepsis or normal group depending on blood culture status. Serial CRP (12-24 hours apart) and complete blood count were then analyzed using independent t-test, Wilcoxon rank-sum test and Receiver operating characteristic (ROC) curves. RESULTS: Of 53 neonates recruited into the present study, 26 (49%) were assigned to sepsis group and the remaining 27 (51%) were assigned to normal group. Baseline characteristics for the two groups were similar except for the higher amount of male participants in sepsis group (p-value 0.006). Most patients in sepsis group (7/26) demonstrated coagulase-negative staphylococci (CoNS) sepsis. The values of 1st CRP and 2nd CRP were significantly higher in sepsis group compared to normal group (p-value < 0.001 and 0.003). From ROC curves, at the cut-off points of 1st CRP > or = 1.90 mg/L and 2nd CRP > or = 1.25 mg/L, the sensitivity were as high as 92.6% and 96.3%, respectively, and the specificity were both at 100%. CONCLUSION: Serial CRP is safe as diagnostic tool to consider antimicrobial treatment in neonatal sepsis with sensitivity of 92.6% and 96.3% for the first CRP cut-off point > or = 1.90 mg/L and the second CRP > or = 1.25 mg/L with 100% positive predictive value. Moreover, these safety profiles might help in reducing overuse of antibiotics with negative predictive value 96.3%.

Efficacy of oral erythromycin for treatment of feeding intolerance in preterm infants.

OBJECTIVE: To determine the efficacy and safety of oral erythromycin (EM) for feeding intolerance in preterm infants < 35 weeks gestation. STUDY DESIGN: In this randomized, double-blinded, placebo-controlled trial, preterm infants with feeding intolerance were randomly allocated to a treatment group given EM ethyl succinate 10 mg/kg every 6 hours for 2 days, followed by 4 mg/kg every 6 hours for another 5 days, or to a control group given placebo. The primary outcome was time to full feeding (150 mL/kg/day) after the start of treatment. RESULTS: Each group comprised 23 preterm infants, almost all of whom were < 32 weeks gestation. Baseline characteristics were similar between the 2 groups. Times to full feeding were significantly shorter and the number of withheld feeds were significantly less in the EM group than the control group; the respective medians (interquartile ranges) were 7 days (6 to 9 days) versus 13 days (9 to 15 days) (P < .001) and 1 episode (0 to 2 episodes) versus 9 episodes (2 to 13 episodes) (P < .001). No significant differences in episodes of sepsis, necrotizing enterocolitis, and cholestasis were observed. CONCLUSIONS: Oral EM was effective and safe for treatment of feeding intolerance in preterm infants.

Vertical dengue infection: case reports and review.

Two vertical dengue infection cases are presented, and 15 others are reviewed. Twelve mothers had fever 0-9 (median, 2) days antepartum. The fevers of 17 neonates occurred at 1-11 (median, 4) days of life and lasted for 1-5 (median, 3) days. Neonatal thrombocytopenia was detected at 1-11 (median, 6) days of life and lasted for 3-18 (median, 6) days; the lowest platelet counts were 5-75 x 10(3) (median, 19 x 10 (3))/mm3. One neonate died.