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.

Neonatal invasive candidiasis in low- and middle-income countries: Data from the NeoOBS study.

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 (HICs). 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 hospitalized infants <60 days postnatal age with sepsis (August 2018-February 2021). A total of 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 gr (interquartile range [IQR]: 990-1692). Only a minority had high-risk criteria, such as being born <28 weeks, 19% (24/127), or birth weight <1000 gr, 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-enrollment 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 low- and middle-income countries with neonatal invasive candidiasis (NIC). Most of them were outside the groups considered at high risk for NIC described in high-income countries. Candida spp. epidemiology was also different. The mortality was high (22%). Further research in these settings is required.

Congenital ocular toxoplasmosis in consecutive siblings / Toxoplasmose ocular congênita em irmãos consecutivos

ABSTRACT Toxoplasma gondii infection can cause ocular manifestations after acquired and congenital disease. We report two cases of symptomatic congenital toxoplasmosis with ocular involvement in non-twin siblings, with a 2-year interval between pregnancies. Vertical transmission of toxoplasmosis in successive pregnancies, which was once considered impossible, is now found to be plausible even in immunocompetent subjects.

RESUMO A infecção pelo Toxoplasma gondii pode causar manifestações oculares tanto após a sua forma congênita quanto a sua forma adquirida. Reportamos aqui dois casos de toxoplasmose congênita sintomática com envolvimento ocular em irmãos não gêmeos, com intervalo de 2 anos entre gestações. A transmissão vertical da toxoplasmose em gestações sucessivas, outrora considerada impossível, é um evento plausível mesmo em indivíduos imunocompetentes.

Congenital ocular toxoplasmosis in consecutive siblings.

Toxoplasma gondii infection can cause ocular manifestations after acquired and congenital disease. We report two cases of symptomatic congenital toxoplasmosis with ocular involvement in non-twin siblings, with a 2-year interval between pregnancies. Vertical transmission of toxoplasmosis in successive pregnancies, which was once considered impossible, is now found to be plausible even in immunocompetent subjects.

Toxoplasma GRA Peptide-Specific Serologic Fingerprints Discriminate Among Major Strains Causing Toxoplasmosis.

The severity of toxoplasmosis depends on a combination of host and parasite factors. Among them, the Toxoplasma strain causing the infection is an important determinant of the disease outcome. Type 2 strains dominate in Europe, whereas in North America type 2, followed by type 3 and 12 strains are commonly isolated from wildlife and patients. To identify the strain type a person is infected with, serological typing provides a promising alternative to the often risky and not always possible biopsy-based DNA methods of genotyping. However, despite recent advances in serotyping, improvements in the sensitivity and specificity are still needed, and it does not yet discriminate among the major Toxoplasma lineages infecting people. Moreover, since infections caused by non-1/2/3 strains have been associated with more severe disease, the ability to identify these is critical. In the present study we investigated the diagnostic potential of an ELISA-based assay using 28 immunogenic Toxoplasma peptides derived from a recent large-scale peptide array screen. Our results show that a discrete number of peptides, derived from Toxoplasma dense granule proteins (GRA3, GRA5, GRA6, and GRA7) was sufficient to discriminate among archetypal strains that infect mice and humans. The assay specifically relies on ratios that compare individual serum reactivities against GRA-specific polymorphic peptide variants in order to determine a "reactivity fingerprint" for each of the major strains. Importantly, nonarchetypal strains that possess a unique combination of alleles, different from types 1/2/3, showed either a non-reactive, or different combinatorial, mixed serum reactivity signature that was diagnostic in its own right, and that can be used to identify these strains. Of note, we identified a distinct "HG11/12" reactivity pattern using the GRA6 peptides that is able to distinguish HG11/12 from archetypal North American/European strain infections.

Congenital cytomegalovirus infection as a cause of sensorineural hearing loss in a highly immune population.

BACKGROUND: The burden of congenital cytomegalovirus (CMV)-associated sensorineural hearing loss (SNHL) in populations with CMV seroprevalence approaching 100% is unknown. The purpose of this study was to assess the rate, associated factors, and predictors of SNHL in CMV-infected infants identified by newborn screening in a highly seropositive maternal population. METHODS: Newborns with positive saliva CMV-DNA that was confirmed by virus isolation in the first 2 weeks of life were enrolled in a prospective follow-up study to monitor hearing outcome. RESULTS: Of 12,195 infants screened, 121 (1%) were infected with CMV and 12 (10%) had symptomatic infection at birth. Hearing function could be assessed in 102/121 children who underwent at least one auditory brainstem evoked response testing at a median age of 12 months. SNHL was observed in 10/102 (9.8%; 95% confidence interval: 5.1-16.7) children. Median age at the latest hearing evaluation was 47 months (12-84 months). Profound loss (>90 dB) was found in 4/5 children with bilateral SNHL while all 5 children with unilateral loss had moderate to severe deficit. The presence of symptomatic infection at birth (odds ratio, 38.1; 95% confidence interval: 1.6-916.7) was independently associated with SNHL after adjusting for intrauterine growth restriction, gestational age, gravidity, and maternal age. Among 10 infants with SNHL, 6 (60%) were born to mothers with nonprimary CMV infection. CONCLUSIONS: Even in populations with near universal immunity to CMV, congenital CMV infection is a significant cause of SNHL demonstrating the importance of CMV as a major cause of SNHL in children worldwide. As in other populations, SNHL is more frequently observed in symptomatic CMV infection.