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).

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole resistant Candida spp. isolates in low-and-middle-income -countries (LMICs) compared to high-income-countries (HIC). We describe the epidemiology, Candida spp. distribution, treatment and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalised infants < 60 days postnatal age with sepsis (August 2018-February 2021). 127 neonates from 14 hospitals in 8 countries with Candida spp. isolated from blood culture were included. Median gestational age of affected neonates was 30 weeks (IQR: 28-34) and median birth weight was 1270 g (IQR: 990–1692). Only a minority had high risk criteria, such as being born < 28 weeks, 19% (24/127), or birth weight < 1000 g, 27% (34/127). The most common Candida species were C. albicans (n = 45, 35%), C. parapsilosis (n = 38, 30%) and Candida auris (n = 18, 14%). The majority of C. albicans isolates were fluconazole susceptible, whereas 59% of C. parapsilosis isolates were fluconazole resistant. Amphotericin B was the most common antifungal used [74% (78/105)], followed by fluconazole [22% (23/105)]. Death by day 28 post-enrolment was 22% (28/127). To our knowledge, this is the largest multi-country cohort of NIC in LMICs. Most of the neonates would not have been considered at high risk for NIC in HICs. A substantial proportion of isolates was resistant to first choice fluconazole. Understanding the burden of NIC in LMIC is essential to guide future research and treatment guidelines. Our study describes neonates from LMIC with neonatal invasive candidiasis (NIC). Most of them were outside the groups considered at high risk for NIC described in HIC. Candida spp. epidemiology was also different. The mortality was high (22%). Further research in these settings is required.

To describe the impact of the 10-valent pneumococcal conjugate vaccine on the pediatric burden of pneumococcal infections, carriage, serotype replacement, and antimicrobial resistance in Brazil since its introduction in 2010. A narrative review of English, Spanish, and Portuguese articles published in online databases and in Brazilian epidemiological surveillance databases was performed. The following keywords were used: Streptococcus pneumoniae, pneumococcal disease, conjugate vaccine, PCV10, antimicrobial resistance, and meningitis. Declines in hospitalization rates of all-cause pneumonia occurred in the target age groups and some age groups not targeted by vaccination early after the use of PCV10. Large descriptive studies of laboratory-confirmed pneumococcal meningitis and hospital-based historical series of hospitalized children with IPD have evidenced a significant impact on disease burden, in-hospital fatality rates, and admission to the intensive care unit before and after the inclusion of the vaccine. Impact data on otitis media is limited and inconsistent; the main benefit remains the prevention of complicated diseases. During the late post-vaccine years, a significant and progressive increase in high-level penicillin non-susceptibility pneumococci has been described. Since 2014 serotype 19A has been the leading serotype in all ages and was responsible for 28.2%–44.6% of all IPD in children under 5 yrs. PCV10 has performed a significant impact on IPD in Brazil since 2010, however, progress has been continuously hampered by replacement. Broader spectrum PCVs could provide expanded direct and indirect protection against ST19A and other additional serotypes of increasing importance if administered to children in the Brazilian National Immunization Program.

In 2020, Brazil became the epicentre of the coronavirus disease (COVID-19) pandemic in Latin America, resulting in an unparalleled health catastrophe. Nevertheless, comprehensive clinical reports in Brazilian children are not available. This retrospective, hospital-based, active surveillance study was performed to identify paediatric patients with COVID-19 who presented at a private academic medical centre in a large urban area between March 2020 and March 2021. Clinical and demographic information was analysed for those requiring hospitalization, those with severe illness and those with clinical syndromes. In total, 964 symptomatic cases were evaluated; of these, 17.7% required hospitalization, and 27.5% of hospitalized cases were classified as severe/critical. Acute bronchiolitis and pneumonia were the most common causes of hospitalization among the severe cases. Twenty-seven hospitalized children fulfilled the diagnostic criteria for multi-system inflammatory syndrome (median age 29 months; 85.2% cases were non-severe). A significant co-existing condition was present in 29% of hospitalized children. The risk of hospitalization was higher in children with at least one comorbidity, children aged <2 years and obese children. Increased risk of severe disease was described among those with leukopenia, leukocytosis or any significant comorbidity. No deaths occurred among the study population. Although most children with COVID-19 experienced mild disease, and no deaths occurred among the study population, a significant proportion of cases required hospitalization and developed severe illness. Obesity, young age, underlying comorbidity, leukopenia and leukocytosis were risk factors for hospitalization or severe disease.

Sickle cell disease (SCD) is an inherited red blood cell disease that results in a multitude of medical complications, including an increased risk of invasive disease caused by encapsulated bacteria, such as Streptococcus pneumoniae. Pneumococcal vaccines have contributed to a significant reduction in pneumococcal disease (PD) in children and adults, including those with SCD. This phase 3 study evaluated the safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine (PCV), in children with SCD. A total of 103 children aged 5 to 17 years with SCD were randomized and received a single dose of V114 or Prevnar 13 (PCV13). Safety was evaluated as the proportion of participants with adverse events (AEs). Serotype-specific immunoglobulin G (IgG) levels and opsonophagocytic activity (OPA) were measured immediately before vaccination and 30 days after vaccination. Overall, the rates of injection-site and systemic AEs reported after vaccination were similar between the vaccination groups. Up to 6 months after vaccination, serious AEs were those expected for patients with SCD, and none were assessed to be vaccine related. IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) for the 13 shared serotypes were generally comparable between recipients of V114 and PCV13. Additionally, V114 induced immune responses to serotypes 22F and 33F, which are not included in PCV13. The safety and tolerability profiles of V114 were consistent with those reported for PCV13. Immune responses following vaccination with V114 were generally comparable to PCV13 for the shared serotypes and higher for unique serotypes 22F and 33F. These results support the use of V114 in children with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03731182.