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).

There are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (C_max) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 μg/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 μg/ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC_0–8) were 12.1, 24.7, 239.4, and 5.1 μg · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed inC_max(geometric mean ratio [GMR]_,2.55; 95% confidence interval [CI], 1.47 to 4.41;P= 0.001) and AUC_0–8(GMR, 2.52; 95% CI, 1.34 to 4.73;P= 0.005). HIV status was associated with lower pyrazinamideC_max(GMR, 0.85; 95% CI, 0.75 to 0.96;P= 0.013) and AUC_0–8(GMR, 0.79; 95% CI, 0.69 to 0.90;P< 0.001) values. No other important differences were observed due to age, weight, prematurity, ethnicity, or gender. In summary, isoniazid and pyrazinamide concentrations in infants compared well with proposed adult target concentrations; ethambutol concentrations were lower but similar to previously reported pediatric studies. The low rifampin exposures require further investigation. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637558.)

Tuberculosis during pregnancy and treatment outcomes are poorly defined in high prevalence tuberculosis and HIV settings. A prospective cohort study of pregnant and postpartum women identified to be routinely on antituberculosis treatment was conducted at Tygerberg Hospital, Cape Town, South Africa, from January 2011 through December 2011. Maternal tuberculosis disease spectrum and tuberculosis-exposed newborns were characterized by maternal HIV status. Maternal tuberculosis treatment outcomes were documented and a multivariable regression model identified predictors of unfavourable tuberculosis treatment outcomes. Infant outcomes were also described. Seventy-four women with tuberculosis, 53 (72%) HIV-infected, were consecutively enrolled; 35 (47%) were diagnosed at delivery or postpartum and 22 (30%) of women reported previous antituberculosis treatment. HIV-infected women were 5.67 times more likely to have extrapulmonary tuberculosis (95% CI 1.18–27.25, p = 0.03). All 5 maternal deaths were amongst HIV-infected women. Birth outcomes were available for 75 newborns (2 sets of twins, missing data for 1 stillbirth). Of the 75 newborns, 49 (65%) were premature and 44 (59%) were low birth weight (LBW; <2500 grams). All 6 infants who died and the 4 stillbirths were born to HIV-infected women. Unfavourable tuberculosis treatment outcomes were documented in 33/74 (45%) women. Unfavourable maternal tuberculosis outcome was associated with delivery of LBW infants (OR 3.83; 95% CI 1.40–10.53, p = 0.009). A large number of pregnant women with tuberculosis presented at a provincial referral hospital. All maternal and infant deaths occurred in HIV-infected women and their newborns. Maternal tuberculosis treatment outcomes were poor.

Epidemiological data on neonatal bloodstream infections (BSI) in sub-Saharan Africa are extremely limited. A comparative analysis of laboratory-confirmed neonatal BSI episodes was conducted retrospectively in two large neonatal units in Botswana and South Africa (January 1 to December 31, 2017). Routine laboratory and ward register data were used to determine BSI rates, the pathogen spectrum, and BSI outcomes. In 2017, the Princess Marina Hospital (PMH) and Tygerberg Hospital (TBH) neonatal units admitted 1187 and 2826 neonates, respectively. The BSI incidence rate was 12.1/1000 patient-days (95% confidence interval (CI) 10.2-14.3) at PMH and 3.5/1000 patient-days (95% CI 2.9-4.1) at TBH (p < 0.0001). Most BSI episodes were hospital-acquired (260/284; 91.6%). The blood culture contamination rate was substantially higher at PMH than TBH (152/1116 (13.6%) vs 122/2559 (4.8%); p < 0.001). The crude mortality rate in neonates with BSI was 21.2% (53/250) and significantly higher at TBH than PMH (38/128 (29.7%) vs 15/122 (12.3%), p = 0.001). Factors independently associated with death were birth weight <1500 g (adjusted odds ratio (aOR) 2.8, 95% CI 1.3-6.4; p = 0.02) and male sex (aOR 2.1, 95% CI 1.1-3.7; p = 0.01). Klebsiella pneumoniae was the dominant BSI pathogen in both units, accounting for two-thirds of BSI, and was associated with a large infection outbreak at PMH. Antibiotic resistance rates were substantial in both neonatal units, particularly for K. pneumoniae (98/122 (80.3%), extended-spectrum beta-lactamase (ESBL)-producers) and Staphylococcus aureus (22/33 (66.7%), methicillin-resistant). BSI rates and associated mortality were substantial in these two neonatal units in sub-Saharan Africa. ESBL-producing K. pneumoniae remains a leading BSI and outbreak pathogen.

Maternal and neonatal tuberculosis (TB) are under-recognised, particularly in settings with a high burden of human immunodeficiency virus (HIV) infection. Retrospective audit of neonates routinely screened for TB in a South African hospital during 2009. Surveillance sources reviewed included routine clinical, laboratory and pharmacy records. Among 70 neonates (60% HIV-exposed) screened for TB, the median gestational age was 35.5 weeks (IQR 33-38), and the median birth weight was 2000 g (IQR 1530-2484). The neonates were grouped according to a history of documented TB exposure: maternal TB in 41/70 (59%), suspected maternal TB in 9/70 (13%), other documented household TB exposure in 5/70 (7%), and no known TB exposure 15/70 (21%). Of the 50 neonates exposed to confirmed or suspected maternal TB, 36 (72%) were initiated on TB chemoprophylaxis, 5 (10%) received TB treatment and 9 (18%) received no intervention. Eight (8/50, 16%) were diagnosed with TB, all of whom were born to mothers with suspected or proven TB. Maternal TB, primarily among HIV-infected women, was the main indication for TB screening of neonates. Routine TB screening of pregnant women and TB care in mothers and infants should be improved in settings with a high burden of TB and HIV.

Isoniazid (INH) is recommended for use as posttuberculosis exposure preventive therapy in children. However, no pharmacokinetic data are available for INH treatment in low-birth-weight (LBW) infants, who undergo substantial developmental and physiological changes. Our objectives in this study were to determine the pharmacokinetic parameters of INH at a dose of 10 mg/kg of body weight/day and to define its pharmacokinetics relative to the arylamine N -acetyltransferase-2 ( NAT2 ) genotype. An intensive prospective pharmacokinetic sampling study was conducted at Tygerberg Children's Hospital, South Africa, in which we measured INH blood plasma concentrations at 2, 3, 4 and 5 h postdose. Twenty LBW infants (14 male, 16 exposed to HIV) were studied. The median birth weight was 1,575 g (interquartile range, 1,190 to 2,035 g) and the median gestational age was 35 weeks (interquartile range, 34 to 38 weeks). The NAT2 acetylation statuses of the infants were homozygous slow (SS) (5 infants), heterozygous intermediate (FS) (11 infants), and homozygous fast (FF) (4 infants). Using a noncompartmental analysis approach, the median maximum drug concentration in blood serum ( C _max ) was 5.63 μg/ml, the time after drug administration to reach C _max T _max ) was 2 h, the area under the concentration-time curve from 2 to 5 h (AUC _2–5 ) was 13.56 μg · h/ml, the half-life ( t _1/2 ) was 4.69 h, and the elimination constant rate ( k _el ) was 0.15 h ⁻¹ . The alanine aminotransferase levels were normal, apart from 2 isolated values at two and three times above the normal levels. Only the three-times-elevated value was repeated at 6 months and normalized. All LBW infants achieved target INH blood plasma concentrations comparable to the adult values. Reduced elimination was observed in smaller and younger infants and in slow acetylators, cautioning against higher doses. The safety data, although limited, were reassuring. More data, however, are required for newborn infants.