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).

Molecular diagnostic of complicated pneumonia in the post-vaccine era.

BACKGROUND: The etiological diagnosis of community-acquired pneumonia (CAP) is still a challenge. We compared the conventional culture method and real-time polymerase chain reaction (RT-PCR) for the identification of Streptococcus pneumoniae in severe pediatric CAP. METHODS: A retrospective hospital-based study was conducted. From 2012 to 2018, we have selected patients who had peripheral blood and/or pleural fluid collected for etiological investigation by RT-PCR. RESULTS: We included 113 children (median age: 3 years; interquartile range 1-6 years). RT-PCR increased the detection rate of S. pneumoniae by 6.5 times using blood samples and eight times using pleural fluid samples. Patients subjected to RT-PCR showed more prolonged hospitalization (p = 0.006), fewer comorbidities (p = 0.03), presence of pleural effusion (p = 0.001), presence of young forms of leukocytes (p = 0.001) and radiograph with characteristics of pneumonia (p = 0.002). The presence of pleural effusion [odds ratio (OR) = 14.7, 95% confidence interval (CI) 1.6-133.9; p = 0.01] and young forms of leukocytes (OR = 8.9, 95% CI 0.9-84.4; p = 0.05) were risk factors for positive RT-PCR pneumococcal when multivariate analysis was performed. CONCLUSIONS: RT-PCR is a reliable method for diagnosing severe CAP using sterile materials and a potentially applicable method in patients with clinical, radiological and non-specific laboratory characteristics of lower respiratory tract infection, especially in complicated cases with pleural effusion.

Vaccination in Pediatric Patients with Sickle-Cell Disease: Uptake Report and Mini-Review.

BACKGROUND: Brazil has one of the highest numbers of births with sickle-cell disease (SCD) in the Americas. Despite the risk of severe illnesses and death due to both vaccine-preventable infections, vaccination uptake in pediatric patients with SCD is unknown. MATERIAL AND METHODS: Children under 18 years with SCD presenting to routine medical consultations had their vaccination status evaluated according to the national recommendations. Data obtained were classified as 'Adequate', 'Delayed' or 'Missing' vaccination and compared among age groups. RESULTS: From 117 children screened, 100 had their vaccination card available. Vaccination coverage of routine vaccines was above 95% for all primary series and both age groups, with varied rates of delays and low missing doses. Among SCD extended vaccination, the most frequently delayed and missed vaccines were those specifically recommended to individuals with SCD as per national guidelines-and particularly those against encapsulated bacteria. Significant and varied rates of missing doses occurred in primary series and booster doses for PPSV23, Hib, menC, hepatitis A and varicella. The average influenza vaccination rate was 69.5%, with higher rates among younger children. CONCLUSIONS: Children with SCD have alarming under-vaccination rates. Basic prevention strategies in Brazil should be reassessed in this specific population.

Latent tuberculosis prevalence, diagnosis and treatment in Multiple Sclerosis as a strategy for reducing infection reactivation during immunosuppressant therapy.

BACKGROUND: Tuberculosis is an infectious disease with a risk of reactivation in Multiple Sclerosis patients on immunosuppressant therapy. Diagnosis and treatment of Latent Tuberculosis Infection (LTBI) prevents the infection. OBJECTIVE: To diagnose and treat LTBI in Multiple Sclerosis (MS). METHODS: Cross-sectional study of the prevalence and treatment of LTBI in MS, between February 2021 and June 2023. LTBI was defined as an absence of symptoms, positive PPD or IGRA and normal chest X-ray. RESULTS: Of the 58 patients with MS, 17 (29.3 %) were diagnosed with LTBI, 15 with PPD > 5 mm and 2 with positive IGRA, 10 (58.8 %) female and 7 (41.1 %) male, mean age of 41.3 (SD ±13.4) years. All patients with LTBI were treated with immunomodulators or immunosuppressants: Fingolimod 5 (29.4 %), Natalizumab 5 (29.4 %), Cladribine 2 (11.8 %), Glatiramer 2 (11.8 %), Ocrelizumab 2 (11.8 %), and Interferon beta 1 (5.9 %). Steroids therapy for relapses, were used in 5/17 (93.8 %) with LTBI and 30/37 (81.1 %) without LTBI. To treat LTBI, 11 (64.7 %) received Isoniazid and 6 (35.3 %) Isoniazid plus Rifapentine. Hepatotoxicity occurred in 3 (17.6 %) with INH. There were no interruptions of ILTB treatment during the study. CONCLUSION: The prevalence of LTBI was found to be high and treatment proved safe.

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.

Impact of PCV10 on pediatric pneumococcal disease burden in Brazil: time for new recommendations?

OBJECTIVE: 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. DATA SOURCE: 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. SUMMARY OF THE FINDINGS: 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. CONCLUSIONS: 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.

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.

Invasive pneumococcal disease among hospitalized children in Brazil before and after the introduction of a pneumococcal conjugate vaccine.

BACKGROUND: Most of the available data on invasive pneumococcal disease in Latin America are derived from laboratory-based surveillance systems. There is a lack of epidemiological data on the disease severity and mortality from hospitalized patients with pneumococcal infection. METHODS: In this hospital-based retrospective historical series of hospitalized children with laboratory-confirmed IPD, we evaluated changes in disease episodes, in-hospital fatality rates, and need for intensive care unit admission after the inclusion of PCV10 in the Brazilian vaccination schedule. Invasive pneumococcal strains isolated by culture were serotyped. Changes over time were assessed, and pre-vaccination (2005-2009) to post-vaccination (2011-2015) disease rates and serotypes were compared. RESULTS: 260 patients with IPD and positive pneumococcal isolates were identified (198 during the pre-PCV10 period). When comparing both periods, hospitalizations were reduced from 20 cases to 5 cases per 10,000 pediatric admissions (p < 0.0001). Likewise, fatalities reduced from 6.6 to 2.0 cases per 10,000 pediatric admissions (p < 0.0001). Pneumonia was the most frequent clinical diagnosis (58%) - of which 49.6% had pleural effusion - followed by meningitis (22%) and bacteremia (15.9%). Overall 30% of cases were sent to ICU, with no percentual changes after PCV10. Additional PCV13 serotypes increased from 7% before vaccine introduction to 21% after PCV10 use. Similarly, serotypes not included in PCV13 increased from 11% to 29%. CONCLUSIONS: There was a significant reduction in the hospitalizations rates, ICU admissions, and fatalities due to IPD after PCV10 introduction in Brazil. Cases due to PCV10 serotypes were reduced, while infections rates caused by non-PCV10 serotypes increased.

Imported hepatopulmonary echinococcosis: first report of Echinococcus granulosus sensu stricto (G1) in Bolivia.

Hepatopulmonary hydatidosis in young children is a rare and atypical presentation of Echinococcus granulosus infection. We report the first case of cystic echinococcosis caused by a microvariant of E. granulosus sensu stricto. Chemotherapy and systemic corticoids were administered before curative surgery was performed. Recurrence was not observed for more than 24 months of follow-up.

First report of two consecutive respiratory syncytial virus outbreaks by the novel genotypes ON-1 and NA-2 in a neonatal intensive care unit.

OBJECTIVE: Respiratory syncytial virus is a pathogen frequently involved in nosocomial outbreaks. Although several studies have reported nosocomial outbreaks in neonatal intensive care units, molecular epidemiology data are scarce. Here, the authors describe two consecutive respiratory syncytial virus outbreaks caused by genotypes ON-1 and NA-2 in a neonatal intensive care unit in São Paulo, Brazil. METHODS: A prospective search for respiratory syncytial virus was performed after diagnosing the index case and four other symptomatic newborns in the neonatal intensive care unit. Nasopharyngeal aspirate samples of all patients in the neonatal intensive care unit were tested for 17 respiratory viruses using real-time reverse transcriptase polymerase chain reaction. Genotyping was performed using nucleotide sequencing. RESULTS: From May to August 2013, two different outbreaks were detected in the neonatal intensive care unit. A total of 20 infants were infected with respiratory syncytial virus-A (ten and 14 with ON-1 and NA-2 genotypes, respectively). The mean age of the infants was 10 days, mean birth weight was 1,961g, and the mean gestational age was 33 weeks. Risk factors (heart disease, lung disease, and prematurity) were present in 80% and 85.7% of infants in the ON-1 and NA-2 groups, respectively. In total, 45.8% of infants were asymptomatic and 20.8% required mechanical ventilation. Coinfections were not detected during the outbreaks. CONCLUSIONS: Infants in a neonatal intensive care unit who develop abrupt respiratory symptoms should be tested for respiratory viruses, especially respiratory syncytial virus. Even in the absence of severe symptoms, respiratory syncytial virus detection can prevent nosocomial transmission through infection control measures. A better understanding of respiratory syncytial virus molecular epidemiology is essential for developing new vaccines and antiviral drugs against respiratory syncytial virus.

Towards understanding global patterns of antimicrobial use and resistance in neonatal sepsis: insights from the NeoAMR network.

OBJECTIVE: To gain an understanding of the variation in available resources and clinical practices between neonatal units (NNUs) in the low-income and middle-income country (LMIC) setting to inform the design of an observational study on the burden of unit-level antimicrobial resistance (AMR). DESIGN: A web-based survey using a REDCap database was circulated to NNUs participating in the Neonatal AMR research network. The survey included questions about NNU funding structure, size, admission rates, access to supportive therapies, empirical antimicrobial guidelines and period prevalence of neonatal blood culture isolates and their resistance patterns. SETTING: 39 NNUs from 12 countries. PATIENTS: Any neonate admitted to one of the participating NNUs. INTERVENTIONS: This was an observational cohort study. RESULTS: The number of live births per unit ranged from 513 to 27 700 over the 12-month study period, with the number of neonatal cots ranging from 12 to 110. The proportion of preterm admissions <32 weeks ranged from 0% to 19%, and the majority of units (26/39, 66%) use Essential Medicines List 'Access' antimicrobials as their first-line treatment in neonatal sepsis. Cephalosporin resistance rates in Gram-negative isolates ranged from 26% to 84%, and carbapenem resistance rates ranged from 0% to 81%. Glycopeptide resistance rates among Gram-positive isolates ranged from 0% to 45%. CONCLUSION: AMR is already a significant issue in NNUs worldwide. The apparent burden of AMR in a given NNU in the LMIC setting can be influenced by a range of factors which will vary substantially between NNUs. These variations must be considered when designing interventions to improve neonatal mortality globally.

Panton-Valentine Positive Staphylococcus aureus in Community-Acquired and Hospital-Acquired Pediatric Infections.

From July 2009 to July 2015, Staphylococcus aureus isolated from pediatric sterile sites were selected. Polymerase chain reaction was used to detect mecA and lukS-PV/lukF-PV genes. The rate of methicillin-resistant Staphylococcus aureus was 37.7%. Ten isolates had the lukS-PV/lukF-PV genes, 2 of which were methicillin-resistant Staphylococcus aureus. Skin and soft tissues infections were significantly associated with lukS-PV/lukF-PV positive isolates, P = 0.008.

High frequency of BF mosaic genomes among HIV-1-infected children from Sao Paulo, Brazil.

HIV-1 genetic diversity information from a pediatric population is scarce. This study enrolled 128 children living with HIV/AIDS, 103 antiretroviral-treated and 25 naive, from the Sao Paulo metropolitan area. Gag, pol and env regions were amplified, and drug resistance mutations, V3 loop, tropism and viral clades were evaluated. Drug resistance mutations among naïve children infected by vertical transmission were uncommon (4.2%), whereas most ARV-experienced children showed extensive mutation patterns. Clade B predominated at the pol region, but the analysis of the three regions concatenated showed 28% with BF mosaic structures. The most common V3 motif was GPGR, followed by GWGR in clade B samples and GPGQ in clade F samples. A predicted X4 phenotype was observed in 27%, without correlation to HIV clade. These findings expand the limited information on molecular characteristics of HIV-1 among children living with HIV/AIDS in the area and may provide information useful for monitoring the epidemic.

Impact of PCV10 on pediatric pneumococcal disease burden in Brazil: time for new recommendations?

Abstract Objective: 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. Data source: 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. Summary of the findings: 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. Conclusions: 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.

Complete Genome Sequences of Five Human Respiratory Syncytial Virus Isolates Collected in Brazil.

Here, we present the complete genome sequences of five human respiratory syncytial virus isolates collected from hospitalized infants suffering from acute respiratory disease. These are the first five complete genome sequences of human respiratory syncytial virus to originate from Brazil.

Early-onset Neonatal Pneumococcal Sepsis: A Fatal Case Report and Brief Literature Review.

Sepsis caused by Streptococcus pneumoniae is rare in neonates although associated with high morbidity and mortality. We report a fatal case of invasive pneumococcal disease in a term neonate whose mother was healthy and did not receive any pneumococcal vaccine. Investigation of the infection source yielded negative results. Acquisition of infection through the birth canal was considered unlikely.

Complete Genome Sequence of a Human Metapneumovirus Isolate Collected in Brazil.

Here, we present the complete genome sequence of a human metapneumovirus isolate collected from a hospitalized infant suffering from acute respiratory disease. This is the first complete genome sequence of human metapneumovirus originating from Brazil.

Complete Genome Sequences of Two Human Parainfluenza Virus Type 3 Isolates Collected in Brazil.

Here, we present the complete genome sequences of two human parainfluenza virus type 3 (HPIV-3) isolates collected from hospitalized infants suffering from acute respiratory disease. These are the first complete genome sequences of HPIV-3 originating from Brazil.

Evaluation of the incidence of occult bacteremia among children with fever of unknown origin.

We reviewed the incidence of occult bacteremia, to identify the most frequent etiological agents of bacteremias in otherwise healthy children from one month to 10 years old, who had fever of unknown origin attended at the emergency ward of an urban, university-affiliated pediatric referral center. This was a retrospective medical record review, evaluating children with fever. Data were collected from the initial visit, when blood cultures, hematological properties and hemosedimentation rates were examined. Fever was considered as the highest temperature assessed in the hospital or reported by the responsible adult. Occult bacteremia was discovered in 1.4% of the 1,051 children evaluated, and the most common etiologic agent was Streptococcus pneumoniae. Total leukocyte count and blood sedimentation rates greater than 30 mm(3) were not predictive factors for occult bacteremia. Fever greater than 39 masculineC was the most important factor for predicting occult bacteremia (P<0.001). The presence of occult bacteremia was significantly correlated with patient hospitalization.

Epidemiological burden of invasive pneumococcal disease in children and adolescents with predisposing risk factors.

OBJECTIVE: Some medical conditions constitute important risk factors for the development of invasive pneumococcal diseases in children and adolescents aged from 5 to 19 years. Conjugate vaccines have potential efficacy in this scenario, but are not available in many Latin American public healthcare systems for this age group. This study aimed to estimate the preventable fraction of invasive pneumococcal diseases among individuals aged from 5 to 19 years with associated risk factors for its development. METHODS: Data regarding the Latin America population, risk factors prevalence and conjugate vaccines efficacy were obtained from the literature. RESULTS: Total population at risk ranged from 17.3 to 64.6 million of individuals and asthma was the most impacting risk factor. According to SIREVA, PCV13 provided a 62.9% serotypes coverage in individuals from 5 to 29 years in 2012, potentially increasing the covered population from [8,338,457-31,057,620] with PCV10 to [10,906,356-40,622,078] with PCV13. To date, according to available efficacy data, the hypothetically immunized population ranged from 11.4 to 42.4 million, representing 7.0% to 26.0% of the total population in this age group. CONCLUSIONS: Vaccination in risk groups should be encouraged, as it potentially contributes to the reduction in the number of cases of invasive pneumococcal disease.