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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

BackgroundSepsis severity scores are used in clinical practice and trials to define risk groups. There are limited data to derive hospital-based sepsis severity scores for neonates and young infants in high-burden low- and middle-income country (LMIC) settings where trials are urgently required. We aimed to create linked sepsis severity and recovery scores applicable to hospitalized neonates and young infants in LMIC which could be used to inform antibiotic trials.Methods & FindingsA prospective observational cohort study was conducted across 19 hospitals in 11 countries in sub-Saharan Africa, Asia, Latin America and Europe. Infants aged 3204 infants were enrolled between 2018-2020. Median age was 5 days (IQR 2-15), 90.4% (n=2,895) were A related NeoSep Recovery Score based on evolving post-baseline clinical signs and supportive care discriminated well between infants who died or survived the following day or subsequent few days. The area under the ROC curve for score on day 2 and death in the following 5 days was 0.82 (95%CI 0.78-0.85) and 0.85 (95%CI 0.78-0.93) in the derivation and validation data, respectively.ConclusionThe baseline NeoSep Severity Score predicted 28-day mortality and could identify infants with high risk of mortality for inclusion in hospital-based sepsis trials. The NeoSep Recovery Score predicts day-by-day inpatient mortality and could, with further validation, help to identify poor response to antibiotics.Author SummaryWhy was this study done?➣Evidence to guide hospital-based antibiotic treatment of sepsis in neonates and young infants is scarce, and clinical trials are particularly urgent in low- and middle-income (LMIC) settings where antimicrobial resistance threatens to undermine existing guidelines➣There is limited data to inform the design of antibiotic trials in LMIC settings, particularly to define risk stratification and inclusion and escalation criteria in hospitalised neonates and young infantsWhat did the researchers do and find?➣To our knowledge this is the first global, prospective, hospital-based observational study of clinically diagnosed neonatal sepsis across 4 continents including LMIC settings, with extensive daily data collection on clinical status, antibiotic use and outcomes.➣There was a high mortality among infants with sepsis in LMIC hospital settings. 4 non-modifiable and 6 modifiable factors predicted mortality and were included in a NeoSep Severity score which defines patterns of mortality risk at baseline➣A NeoSep Recovery Score including the same modifiable factors (with the addition of cyanosis) predicted mortality on the following day during the course of treatment.What do these findings mean?➣The NeoSep Severity Score and NeoSep Recovery score are now informing inclusion and escalation criteria in the NeoSep1 antibiotic trial (ISRCTN48721236) which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis➣The NeoSep Severity Score could be used to predict mortality at baseline in future studies of targeting resources in routine care. With further validation, the NeoSep Recovery Score could potentially be used to identify poor response to empiric antibiotic treatment

BackgroundNeonatal sepsis is a leading cause of child mortality, and increasing antimicrobial resistance threatens progress towards the Sustainable Development Goals. Evidence to guide antibiotic treatment for sepsis in neonates and young infants from randomized controlled trials or observational studies in low- and middle-income countries (LMICs) is scarce. We aimed to describe patterns of antibiotic use, pathogens and outcomes in LMIC hospital settings globally to inform future clinical trials on the management of neonatal sepsis.Methods & FindingsHospitalised infants aged 206 different empiric antibiotic combinations were used, which were structured into 5 groups that were developed from the World Health Organisation (WHO) AWaRe classification. 25.9% (n=814) of infants started a WHO first line regimen (Group 1 -Access, penicillin-based regimen) and 13.8% (n=432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2- ‘Low’ Watch). The largest group (34.0%, n=1068) 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) started a Reserve antibiotic (Group 5, largely colistin-based). Predictors of starting non-WHO recommended regimens included lower birth weight, longer in-hospital stay, central vascular catheter use, previous culture positive sepsis or antibiotic exposure, previous surgery and greater sepsis severity. 728/2880 (25.3%) of initial regimens in Group 1-4 were escalated, mainly to carbapenems, and usually for clinical indications (n=480; 65.9%).564 infants (17.6%) isolated a pathogen from their baseline blood culture, of which 62.9% (n=355) had a Gram-negative organism, predominantlyKlebsiella pneumoniae(n=132) andAcinetobacterspp. (n=72). These leading Gram-negatives were both mostly resistant to WHO-recommended regimens, and also resistant to carbapenems in 32.6% and 71.4% of cases respectively. MRSA accounted for 61.1% ofStaphylococcus aureus(n=54) isolates.Overall, 350/3204 infants died (11.3%; 95%CI 10.2-12.5%), with 17.7% case fatality rate among infants with a pathogen in baseline culture (95%CI 14.7-20.1%, n=99/564). Gram-negative infections accounted for 75/99 (75.8%) of pathogen-positive deaths, especiallyKlebsiella pneumoniae(n=28; 28.3%), andAcinetobacterspp. (n=24; 24.2%).ConclusionA very wide range of antibiotic regimens are now used to treat neonatal sepsis globally. There is common use of higher-level Watch antibiotics, frequent early switching and very infrequent de-escalation of therapy. Future hospital based neonatal sepsis trials will ideally need to account for the multiple regimens used as standard of care globally and include both empiric first line regimens and subsequent switching in the trial design.Author SummaryWhy was this study done?➢Increasing trends in antimicrobial resistance (AMR) disproportionately affect neonates and young infants with sepsis in LMIC settings and undermine the effectiveness of WHO-recommended antibiotics.➢Despite this, longitudinal data on antibiotic management strategies and outcomes of affected hospitalised neonates and young infants in LMIC settings are extremely limited, impeding the design of robust antibiotic trials.What did the researchers do and find?➢To our knowledge this is the first global, prospective, hospital-based observational study of clinically diagnosed neonatal sepsis across 4 continents including LMIC settings, with daily data on clinical status, antibiotic use and outcomes.➢There was a high mortality among infants with culture positive sepsis (almost 1 in 5), and a significant burden of antibiotic resistance.➢This study highlights wide variations in standard of care for sepsis in neonates and young infants with more than 200 different antibiotic combinations, significant divergence from WHO-recommended regimens, and frequent switching of antibiotics.What do these findings mean?➢These data demonstrate that patterns of routine antibiotic use are now markedly divergent from global guidance➢There is an urgent need for randomised controlled trials to address optimal empiric first and second line antibiotic treatment strategies in LMIC hospital settings with a significant AMR burden.➢Data from this study can inform the design of multicentre hospital-based neonatal antibiotic trials in LMIC settings.➢The wide range of multiple antibiotic regimens routinely used as Standard of Care (SOC) suggests the need for novel trial designs.

ObjectiveTo 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).DesignA 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.Setting39 NNUs from 12 countries.PatientsAny neonate admitted to one of the participating NNUs.InterventionsThis was an observational cohort study.ResultsThe 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 ConclusionAMR 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.

Background: Neonatal sepsis is associated with high mortality, but there is limited clinical data on outcomes in hospital facilities in low and middle income countries (LMIC). The NeoOBS study aimed to determine the clinical features, pathogens and clinical outcomes of infants presenting with neonatal sepsis in hospitals globally. Methods: Infants

IntroductionThe success of antiretroviral treatment (ART) programs can be compromised by high rates of patient loss to follow-up (LTFU). We assessed the incidence and risk factors of LTFU in a large cohort of HIV-infected children receiving ART in Thailand.MethodsAll children participating in a multicenter cohort (NCT00433030) between 1999 and 2014 were included. The date of LTFU was 9 months after the last contact date. ART interruption was defined as ART discontinuation for more than 7 days followed by resumption of treatment. Baseline and time-dependent risk factors associated with LTFU were identified using Fine and Gray competing risk regression models with death or referral to another hospital as competing events.ResultsOf 873 children who were followed during a median of 8.6 years (interquartile range 4.5-10.6), 196 were LTFU, 73 died, and 195 referred. The cumulative incidence of LTFU was 2.9% at 1 year, 7.3% at 5 years and 22.2% at 10 years. Children aged 13 years and more had a 3-fold higher risk (95% confidence interval 2.06-4.78) of LTFU than those younger. Children who had interrupted ART within the previous year had a 2.5-fold higher risk (1.12-5.91) than those who had not. The risk of LTFU was lower in children stunted (height-for-age Z-scores ConclusionAdolescence, ART interruption and absence of growth deficit were associated with LTFU. These may be warnings that should draw clinicians' attention and possibly trigger specific interventions. Children with no significant growth retardation may also be at risk of LTFU.

From 1996 to 2001, nineteen episodes of bacteremia due to group B Streptococci (GBS) were diagnosed in Siriraj Hospital, Mahidol University. The incidence of early onset group B streptococcal disease (EOD) was 0.27 cases/1,000 live births in 1996, and decreased to 0.10 cases/1,000 live births in 2001. The incidence of the late onset disease (LOD) was 0.05 cases/1,000 in 1996, and there has been none since 1998. All of the infants were inborn. Low birth weight was found in 53 per cent of the infants. Fifty-eight per cent of infants were male. Forty-seven per cent of the infants were born prematurely. None of the mothers had antenatal GBS screening. Only one mother received one dose of intrapartum antibiotic prophylaxis. No risk factor could be identified in 72 per cent of the mothers. EOD accounted for 79 per cent of all infants with GBS infections, with a mortality rate of 40 per cent. All of them died within the first 72 hours of life. Most EOD infants developed disease manifestations within 12 hours of life. Most common clinical manifestations were respiratory distress (74%), temperature instability (68%), cyanosis (63%), hypotension (42%) and lethargy (42%). Only one infant with EOD had meningitis. There were two infants in the LOD group; one of whom had cellulitis, and the other had meningitis. Neutropenia was noted in 42 per cent of all infants. Radiographic studies suggested a diffuse reticulogranular pattern or ground glass appearance in 38 per cent. The chest X-ray was interpreted as normal in 25 per cent of the infants. In conclusion, the incidence of GBS infection in newborn infants in Thailand is still very low but with a very high mortality. Prematurity accounts for almost half of the cases. Even though antepartum screening with intrapartum antibiotic chemoprophylaxis has been recommended in developed counties, its benefit and cost needs to be further investigated in Thailand.