Prospective antimicrobial stewardship interventions by multidisciplinary teams to reduce neonatal antibiotic use in South Africa: the Neonatal Antimicrobial Stewardship (NeoAMS) study.

BACKGROUND: Hospitalised neonates are vulnerable to infection and have high rates of antibiotic utilisation. METHODS: Fourteen South African neonatal units (seven public, seven private sector) assembled multidisciplinary teams involving neonatologists, microbiologists, pharmacists, and nurses to implement prospective audit and feedback neonatal antimicrobial stewardship (NeoAMS) interventions. The teams attended seven online training sessions. Pharmacists conducted weekday antibiotic prescription reviews in the neonatal intensive care unit and/or neonatal wards providing feedback to the clinical teams. Anonymised demographic and NeoAMS interventions data were aggregated for descriptive purposes and statistical analysis. FINDINGS: During the 20-week NeoAMS intervention in 2022, 565 neonates were enrolled. Pharmacists evaluated seven hundred antibiotic prescription episodes; rule-out sepsis (180; 26%) and culture-negative sepsis (138; 20%) were the most frequent indications for antibiotic prescription. For infection episodes with an identified pathogen, only 51% (116/229) of empiric treatments provided adequate antimicrobial coverage. Pharmacists recommended 437 NeoAMS interventions (0·6 per antibiotic prescription episode), with antibiotic discontinuation (42%), therapeutic drug monitoring (17%), and dosing (15%) recommendations most frequent. Neonatal clinicians' acceptance rates for AMS recommendations were high (338; 77%). Mean antibiotic length of therapy decreased by 24% from 9·1 to 6·9 days (0·1 day decrease per intervention week; p=0·001), with the greatest decline in length of therapy for culture-negative sepsis (8·2 days (95%CI 5·7-11·7) to 5·9 days (95% CI 4·6-7·5); p=0·032). INTERPRETATION: This neonatal AMS programme was successfully implemented in heterogenous and resource-limited settings. Pharmacist-recommended AMS interventions had high rates of clinician acceptance. The NeoAMS intervention significantly reduced neonatal antibiotic use, particularly for culture-negative sepsis. FUNDING: A grant from Merck provided partial support.

A Retrospective Study Evaluating Neonatal Vancomycin Loading Doses to Achieve a Therapeutic Target.

BACKGROUND: Vancomycin is a glycopeptide antibiotic that has been used to treat hospital-acquired gram-positive infections for more than 5 decades. However, the literature is divided regarding the therapeutic advantages of vancomycin loading doses in neonates. OBJECTIVES: This study aimed to investigate the effect of vancomycin loading doses on therapeutic target attainment in neonates with sepsis. METHODS: A retrospective cohort study was conducted to compare the vancomycin target attainment (area under the curve 0-24 hours/minimum inhibitory concentration ≥400) in neonates before and after the 2019 change in vancomycin prescription guidelines at a neonatal unit in Cape Town, South Africa. As the standard of care, Bayesian modelling software was used to compute the area under the curve from the trough concentrations. RESULTS: Two hundred ten neonates were included. Multivariate regression analysis showed a 2-fold increase in the odds of target attainment among neonates receiving a loading dose of vancomycin. Early target attainment (within 8-12 hours of treatment initiation) was significantly higher in the loading dose group compared with the no loading dose group [97/105 (92.4%) versus 64/105 (61.0%); P < 0.001]. However, the overall proportion of neonates achieving target attainment at 24 hours was similar between groups [73/105 (69.5%) in the loading dose group versus 62/105 (59.0%) in the no loading dose group; P = 0.110]. The nephrotoxicity rates were low [2/105 (1.9%) in the loading dose group and 2/105 (1.9%) in the no loading dose group]. CONCLUSIONS: The addition of a vancomycin loading dose to neonates may facilitate early therapeutic target attainment.

Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial.

INTRODUCTION: Preterm pre-eclampsia is a leading cause of maternal morbidity and mortality. The Pre-eclampsia Intervention 2 (PI 2) trial suggested that metformin sustained release (XR) may prolong gestation by a week in pregnant women undergoing expectant management (7.6 days, geometric mean ratio 1.39, 95% CI 0.99 to 1.95; p=0.057). These findings should be confirmed with a larger sample size, and we need to know if such a prolongation improves neonatal outcome. Here, we describe the protocol for such a follow-up trial. METHODS: The PI 3 trial is a phase III, intention-to-treat, double-blind, placebo-controlled randomised clinical trial to assess if metformin XR can prolong gestation and improve neonatal outcomes in women undergoing expectant management for preterm pre-eclampsia. We will recruit women who are between 26+0 and 31+6 weeks pregnant. Women will be randomised to receive either 3 g metformin XR or an identical placebo in divided daily doses. The primary outcome is prolongation of pregnancy. Secondary outcomes are neonatal birth weight and length of neonatal care admission (an indicator of neonatal health at birth). All other outcomes will be exploratory. We will record tolerability and adverse events. We plan a sample size of 500 participants to be powered for the primary and secondary outcomes. ETHICS AND DISSEMINATION: PI 3 has ethical approval (Health Research Ethics Committee 2, Stellenbosch University, Protocol number M21/03/007, Project ID 21639, Federal Wide Assurance Number 00001372, Institutional Review Board Number IRB0005239), and is registered with the Pan African Clinical Trial Registry (PACTR202104532026017) and the South African Medicine Control Council (20211211). Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: PACTR202104532026017).

Management of the infant born to a mother with tuberculosis: a systematic review and consensus practice guideline.

Infants born to mothers with tuberculosis disease are at increased risk of developing tuberculosis disease themselves. We reviewed published studies and guidelines on the management of these infants to inform the development of a consensus practice guideline. We searched MEDLINE, CINAHL, and Cochrane Library from database inception to Dec 1, 2022, for original studies reporting the management and outcome of infants born to mothers with tuberculosis. Of the 521 published papers identified, only three met inclusion criteria and no evidence-based conclusions could be drawn from these studies, given their narrow scope, variable aims, descriptive nature, inconsistent data collection, and high attrition rates. We also assessed a collection of national and international guidelines to inform a consensus practice guideline developed by an international panel of experts from different epidemiological contexts. The 16 guidelines reviewed had consistent features to inform the expert consultation process. Two management algorithms were developed-one for infants born to mothers considered potentially infectious at the time of delivery and another for mothers not considered infectious at the time of delivery-with different guidance for high and low tuberculosis incidence settings. This systematic review and consensus practice guideline should facilitate more consistent clinical management, support the collection of better data, and encourage the development of more studies to improve evidence-based care.

Safety and efficacy of whole-body chlorhexidine gluconate cleansing with or without emollient in hospitalised neonates (NeoCHG): a multicentre, randomised, open-label, factorial pilot trial.

Background: Healthcare-associated infections account for substantial neonatal in-hospital mortality. Chlorhexidine gluconate (CHG) whole body skin application could reduce sepsis by lowering bacterial colonisation density, although safety and optimal application regimen is unclear. Emollients, including sunflower oil, may independently improve skin condition, thereby reducing sepsis. We aimed to inform which concentration and frequency of CHG, with or without emollient, would best balance safety and the surrogate marker of efficacy of reduction in bacterial colonisation, to be taken forward in a future pragmatic trial evaluating clinical outcomes of sepsis and mortality. Methods: In this multicentre, randomised, open-label, factorial pilot trial, neonates in two hospital sites (South Africa, Bangladesh) aged 1-6 days with gestational age ≥ 28 weeks and birthweight 1000-1999 g were randomly assigned in a factorial design stratified by site to three different concentrations of CHG (0.5%, 1%, and 2%), with or without emollient (sunflower oil) applied on working days vs alternate working days. A control arm received neither product. Caregivers were unblinded although laboratory staff were blinded to randomisation Co-primary outcomes were safety (change in neonatal skin condition score incorporating dryness, erythema, and skin breakdown) and efficacy in reducing bacterial colonisation density (change in total skin bacterial log10 CFU from randomisation to day-3 and day-8). The trial is registered at the ISRCTN registry, ISRCTN 69836999. Findings: Between Apr 12 2021 and Jan 18 2022, 208 infants were randomised and 198 were included in the final analysis. Skin condition scores were low with mean 0.1 (sd = 0.3; N = 208) at baseline, 0.1 (sd = 0.3; N = 199) at day 3 and 0.1 (sd = 0.3; N = 189) at day 8, with no evidence of differences between concentration (1% CHG vs 0.5% estimate = -0.3, 95% CI = (-1.2, 0.6), p = 0.55. 2% CHG vs 0.5% CHG estimate = 0.5 (-0.4, 1.4), p = 0.30), increasing frequency (estimate = -0.4; 95% CI = (-1.1, 0.4), p = 0.33), emollient (estimate = -0.5, (-1.2, 0.3), p = 0.23) or with control (estimate = -0.9, (-2.3, 0.4), p = 0.18). Mean log10 CFU was 4.9 (sd = 3.0; N = 208) at baseline, 6.3 (sd = 3.1; N = 198) at day 3 and 8.4 (sd = 2.6; N = 183) with no evidence of differences between concentration (1% CHG vs 0.5% estimate = -0.4; 95% CI = (-1.1, 0.23); p = 0.23. 2% CHG vs 0.5% CHG estimate = 0.0 (-0.6, 0.6), p = 0.96), with increasing frequency (estimate = -0.4; 95% CI = (-0.9, 0.2); p = 0.17), with emollient (estimate = 0.4, 95% CI = (-0.2, 0.9); p = 0.18) or with control (estimate = -0.2, 95% CI = (-1.3, 0.9); p = 0.73). By day-8, overall 158/183 (86%) of neonates were colonised with Enterobacterales, and 72/183 (39%) and 69/183 (9%) with Klebsiella spp resistant to third-generation cephalosporin and carbapenems, respectively. There were no CHG-related SAEs, emollient-related SAEs, grade 3 or 4 skin scores or grade 3 or 4 hypothermias. Interpretation: In this pilot trial of CHG with or without sunflower oil, no safety issues were identified, and further trials examining clinical outcomes are warranted. The relatively late start application of emollient, at a mean of 3.8 days of life, may have reduced the impact of the intervention although no subgroup effects were detected. There was no clear evidence in favour of a specific concentration of chlorhexidine, and there was rapid colonisation with Enterobacterales with frequent antimicrobial resistance, regardless of skin application regimen. Funding: The MRC Joint Applied Global Health award, the Global Antibiotic Research and Development Partnership (GARDP), MRC Clinical Trials Unit core funding (UKRI) and St. George's, University of London.

Paediatric abacavir-lamivudine fixed-dose dispersible tablets and ritonavir-boosted lopinavir granules in neonates exposed to HIV (PETITE study): an open-label, two-stage, single-arm, phase 1/2, pharmacokinetic and safety trial.

BACKGROUND: Existing solid antiretroviral fixed-dose combination formulations are preferred over liquid formulations in children, but their suitability for neonates is unknown. We evaluated the pharmacokinetics and safety of paediatric abacavir-lamivudine fixed-dose dispersible tablets and ritonavir-boosted lopinavir granules in neonates. METHODS: In this open-label, two-stage, single-arm, phase 1/2, pharmacokinetic and safety trial, generic abacavir- lamivudine (120:60 mg) double-scored dispersible tablets and lopinavir boosted with ritonavir (40:10 mg) granules were studied. Neonates exposed to HIV (≥37 weeks gestational age) of no more than 3 days of age with birthweights of 2000-4000 g were identified through routine care in a tertiary hospital in Cape Town, South Africa. In stage 1, the pharmacokinetics and safety of two single doses were assessed to select the multidose strategy for stage 2. Neonates received a single dose of abacavir-lamivudine (30:15 mg, a quarter of a tablet) and lopinavir boosted with ritonavir (40:10 mg - one sachet) orally between 3 days and 14 days of age, and a second dose of a quarter tablet of abacavir-lamivudine and lopinavir boosted with ritonavir (80:20 mg, two sachets) 10-14 days later in stage 1. The multidose strategy selected in stage 2 was a quarter of the abacavir-lamivudine (30:15 mg) fixed-dose dispersible tablet once per day and two sachets of the lopinavir boosted with ritonavir (80:20 mg) granules twice per day from birth to age 28 days. In both stages two intensive pharmacokinetic visits were done, one at less than 14 days of life (pharmacokinetics 1) and another 10-14 days later (pharmacokinetics 2). Safety visits were done 1-2 weeks after each pharmacokinetic visit. Primary objectives were to assess pharmacokinetics and safety of abacavir, lamivudine, and lopinavir. Pharmacokinetic endpoints were area under the concentration time curve (AUC), maximum concentration, and concentration at end of dosing interval in all participants with at least one evaluable pharmacokinetic visit. Safety endpoints included grade 3 or worse adverse events, and grade 3 or worse treatment-related adverse events, occurring between study drug initiation and end of study. This completed trial is registered with the Pan African Clinical Trials Registry (PACTR202007806554538). FINDINGS: Between Aug 18, 2021, and Aug 18, 2022, 24 neonates were enrolled into the trial and received study drugs. Eight neonates completed stage 1, meeting interim pharmacokinetic and safety criteria. In stage 2, 16 neonates received study drugs. Geometric mean abacavir and lamivudine exposures (AUC0-24) were higher at 6-14 days (51·7 mg × h/L for abacavir and 17·2 mg × h/L for lamivudine) than at 19-24 days of age (25·0 mg × h/L and 11·3 mg × h/L), whereas they were similar for lopinavir over this period (AUC 0-12 58·5 mg × h/L vs 46·4 mg × h/L). Abacavir geometric mean AUC0-24 crossed the upper reference range at pharmacokinetics 1, but rapidly decreased. Lamivudine and lopinavir AUC0-tau were within range. No grade 2 or worse adverse events were related to study drugs. One neonate had a grade 1 prolonged corrected QT interval using the Fridericia method that spontaneously resolved. INTERPRETATION: Abacavir-lamivudine dispersible tablets and ritonavir-boosted lopinavir granules in neonates were safe and provided drug exposures similar to those in young infants. Although further safety data are needed, this regimen presents a new option for HIV prevention and treatment from birth. Accelerating neonatal pharmacokinetic studies of novel antiretroviral therapies is essential for neonates to also benefit from state-of-the-art treatments. FUNDING: Unitaid.

Safety and Pharmacokinetics of Lopinavir/Ritonavir Oral Solution in Preterm and Term Infants Starting Before 3 Months of Age.

BACKGROUND: Study of liquid lopinavir/ritonavir (LPV/r) in young infants has been limited by concerns for its safety in neonates. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1106 was a phase IV, prospective, trial evaluating the safety and pharmacokinetics of antiretroviral medications administered according to local guidelines to South African preterm and term infants <3 months of age. Safety evaluation through 24-week follow-up included clinical, cardiac and laboratory assessments. Pharmacokinetic data from P1106 were combined with data from International Maternal Pediatric Adolescent AIDS Clinical Trials Network studies P1030 and P1083 in a population pharmacokinetics model used to simulate LPV exposures with a weight-band dosing regimen in infants through age 6 months. RESULTS: Safety and pharmacokinetics results were similar in 13/28 (46%) infants initiating LPV/r <42 weeks postmenstrual age (PMA) and in those starting ≥42 weeks PMA. LPV/r was started at a median (range) age of 47 (13-121) days. No grade 3 or higher adverse events were considered treatment related. Modeling and simulation predicted that for infants with gestational age ≥27 weeks who receive the weight-band dosing regimen, 82.6% will achieve LPV trough concentration above the target trough concentration of 1.0 µg/mL and 56.6% would exceed the observed adult lower limit of LPV exposure of 55.9 µg·h/mL through age 6 months. CONCLUSIONS: LPV/r oral solution was safely initiated in a relatively small sample size of infants ≥34 weeks PMA and >2 weeks of life. No serious drug-related safety signal was observed; however, adrenal function assessments were not performed. Weight-band dosing regimen in infants with gestational age ≥27 weeks is predicted to result in LPV exposures equivalent to those observed in other pediatric studies.

Early-versus late-onset sepsis in neonates - time to shift the paradigm?

BACKGROUND: Neonatal sepsis is traditionally classified as early-onset sepsis (EOS) and late-onset sepsis (LOS) disease categories. This paradigm was based on observed epidemiological data from high income settings. However, increasing availability of microbiology results from diverse settings challenges these assumptions, necessitating re-examination of neonatal sepsis classifications. OBJECTIVES: To review the literature describing the aetiology of EOS and LOS in hospitalized neonates with stratification of pathogen spectrum by low- (LIC), middle- (MIC) and high-income (HIC) country settings, to critically re-examine the continued appropriateness of the 'EOS vs. LOS' sepsis paradigm in all settings. SOURCES: PubMed was searched for peer-reviewed English full-text articles published from inception up until 8 August 2022. CONTENT: Studies often report on either EOS or LOS, rather than both. We identified only 49 original articles reporting on pathogen distribution of both EOS and LOS in the same hospital setting. Clear differences in sepsis aetiology were shown between LIC, MIC and HIC settings, with increasing importance of Klebsiella pneumoniae and decreasing importance of Group B Streptococcus in the first 72 hours of life in LIC and MIC. IMPLICATIONS: The concept of 'EOS vs. LOS' may be less useful for predicting the pathogen spectrum of neonatal sepsis in LIC and MIC, but the paradigm has shaped reporting of neonatal sepsis, and our understanding. Future neonatal sepsis reporting should utilize strengthening the reporting of observational studies in epidemiology for newborn infection (STROBE-NI) reporting guidelines and clearly describe timing of infection by day, and variation in pathogen spectrum across the neonatal period. Data identified in this review challenge the generalizability of the prevailing EOS/LOS paradigm in LIC and MIC.

Cost-effectiveness of broadly neutralizing antibodies for infant HIV prophylaxis in settings with high HIV burdens: a simulation modeling study.

Introduction: Approximately 130 000 infants acquire HIV annually despite global maternal antiretroviral therapy scale-up. We evaluated the potential clinical impact and cost-effectiveness of offering long-acting, anti-HIV broadly neutralizing antibody (bNAb) prophylaxis to infants in three distinct settings. Methods: We simulated infants in Côte d'Ivoire, South Africa, and Zimbabwe using the Cost-Effectiveness of Preventing AIDS Complications-Pediatric (CEPAC-P) model. We modeled strategies offering a three-bNAb combination in addition to WHO-recommended standard-of-care oral prophylaxis to infants: a) with known, WHO-defined high-risk HIV exposure at birth (HR-HIVE); b) with known HIV exposure at birth (HIVE); or c) with or without known HIV exposure (ALL). Modeled infants received 1-dose, 2-doses, or Extended (every 3 months through 18 months) bNAb dosing. Base case model inputs included 70% bNAb efficacy (sensitivity analysis range: 10-100%), 3-month efficacy duration/dosing interval (1-6 months), and $20/dose cost ($5-$100/dose). Outcomes included pediatric HIV infections, life expectancy, lifetime HIV-related costs, and incremental cost-effectiveness ratios (ICERs, in US$/year-of-life-saved [YLS], assuming a ≤50% GDP per capita cost-effectiveness threshold). Results: The base case model projects that bNAb strategies targeting HIVE and ALL infants would prevent 7-26% and 10-42% additional pediatric HIV infections, respectively, compared to standard-of-care alone, ranging by dosing approach. HIVE-Extended would be cost-effective (cost-saving compared to standard-of-care) in Côte d'Ivoire and Zimbabwe; ALL-Extended would be cost-effective in South Africa (ICER: $882/YLS). BNAb strategies targeting HR-HIVE infants would result in greater lifetime costs and smaller life expectancy gains than HIVE-Extended. Throughout most bNAb efficacies and costs evaluated in sensitivity analyses, targeting HIVE infants would be cost-effective in Côte d'Ivoire and Zimbabwe, and targeting ALL infants would be cost-effective in South Africa. Discussion: Adding long-acting bNAbs to current standard-of-care prophylaxis would be cost-effective, assuming plausible efficacies and costs. The cost-effective target population would vary by setting, largely driven by maternal antenatal HIV prevalence and postpartum incidence.

Perinatal tuberculosis-An approach to an under-recognized diagnosis.

Tuberculosis (TB) in young infants (<3 months of age), often referred to as perinatal TB, is underdiagnosed, leading to severe morbidity and high mortality. Perinatal TB includes both congenital and postnatal transmission of Mycobacterium tuberculosis. We aimed to increase an awareness of TB in neonates and young infants and to provide guidance on the assessment and management when in contact with mothers with TB during or soon after pregnancy. Approximately 217,000 pregnant women develop TB annually; if they are not diagnosed and treated during pregnancy, their infants are at high risk of adverse birth outcomes and TB disease. Although safe and effective antituberculosis treatment regimens are available during pregnancy, the diagnosis of TB is challenging. Infants born to mothers newly diagnosed with TB, not receiving any effective treatment or with cultures not yet negative, should be assessed for TB disease or M. tuberculosis infection. TB preventive therapy should be instituted if the infant is clinically well but exposed to TB, while prompt initiation of TB treatment is essential if TB disease is presumed. HIV status of mother and infant should be considered as this will affect the management. Further research is needed for the diagnosis and prevention of TB during pregnancy, an early diagnosis of TB in infants, and antituberculosis drug pharmacokinetics in young infants.

Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Development and internal validation of a Neonatal Healthcare-associated infectiOn Prediction score (NeoHoP score) for very low birthweight infants in low-resource settings: a retrospective case-control study.

BACKGROUND AND OBJECTIVES: Early diagnosis of neonatal infection is essential to prevent serious complications and to avoid unnecessary use of antibiotics. The prevalence of healthcare-associated infections (HAIs) among very low birthweight (VLBW; <1500 g) infants is 20%; and the mortality in low-resource settings can be as high as 70%. This study aimed to develop an Infection Prediction Score to diagnose bacterial HAIs. METHODS: A retrospective cohort of VLBW infants investigated for HAI was randomised into two unmatched cohorts. The first cohort was used for development of the score, and the second cohort was used for the internal validation thereof. Potential predictors included risk factors, clinical features, interventions, and laboratory data. The model was developed based on logistic regression analysis. RESULTS: The study population of 655 VLBW infants with 1116 episodes of clinically suspected HAIs was used to develop the model. The model had five significant variables: capillary refill time >3 s, lethargy, abdominal distention, presence of a central venous catheter in the previous 48 hours and a C reactive protein ≥10 mg/L. The area below the receiver operating characteristic curve was 0.868. A score of ≥2 had a sensitivity of 54.2% and a specificity of 96.4%. CONCLUSION: A novel Infection Prediction Score for HAIs among VLBW infants may be an important tool for healthcare providers working in low-resource settings but external validation needs to be performed before widespread use can be recommended.

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.

Antiretroviral postnatal prophylaxis to prevent HIV vertical transmission: present and future strategies.

INTRODUCTION: Maternal antiretroviral therapy (ART) with viral suppression prior to conception, during pregnancy and throughout the breastfeeding period accompanied by infant postnatal prophylaxis (PNP) forms the foundation of current approaches to preventing vertical HIV transmission. Unfortunately, infants continue to acquire HIV infections, with half of these infections occurring during breastfeeding. A consultative meeting of stakeholders was held to review the current state of PNP globally, including the implementation of WHO PNP guidelines in different settings and identifying the key factors affecting PNP uptake and impact, with an aim to optimize future innovative strategies. DISCUSSION: WHO PNP guidelines have been widely implemented with adaptations to the programme context. Some programmes with low rates of antenatal care attendance, maternal HIV testing, maternal ART coverage and viral load testing capacity have opted against risk-stratification and provide an enhanced PNP regimen for all infants exposed to HIV, while other programmes provide infant daily nevirapine antiretroviral (ARV) prophylaxis for an extended duration to cover transmission risk throughout the breastfeeding period. A simplified risk stratification approach may be more relevant for high-performing vertical transmission prevention programmes, while a simplified non-risk stratified approach may be more appropriate for sub-optimally performing programmes given implementation challenges. In settings with concentrated epidemics, where the epidemic is often driven by key populations, infants who are found to be exposed to HIV should be considered at high risk for HIV acquisition. All settings could benefit from newer technologies that promote retention during pregnancy and throughout the breastfeeding period. There are several challenges in enhanced and extended PNP implementation, including ARV stockouts, lack of appropriate formulations, lack of guidance on alternative ARV options for prophylaxis, poor adherence, poor documentation, inconsistent infant feeding practices and in inadequate retention throughout the duration of breastfeeding. CONCLUSIONS: Tailoring PNP strategies to a programmatic context may improve access, adherence, retention and HIV-free outcomes of infants exposed to HIV. Newer ARV options and technologies that enable simplification of regimens, non-toxic potent agents and convenient administration, including longer-acting formulations, should be prioritized to optimize the effect of PNP in the prevention of vertical HIV transmission.

Colistin use in a carbapenem-resistant Enterobacterales outbreak at a South African neonatal unit.

Background: Colistin is increasingly prescribed for neonates with carbapenem-resistant Enterobacterales (CRE) infections. Objectives: We described patient demographics, infection episodes, treatment and clinical outcomes, colistin related adverse events and relatedness of isolates in neonates with clinically confirmed or clinically suspected CRE infections. Method: The authors retrospectively reviewed culture-confirmed and clinically suspected culture-negative CRE infections at a South African neonatal unit during a CRE outbreak. Results: Fifty-three neonates (median gestational age 29 weeks and birth weight 1185 g) were included. Twenty-three of 53 neonates (43%) had culture-confirmed CRE (17 received colistin; 6 died without receiving colistin) and 30 (57%) received colistin for clinically suspected CRE infection but were ultimately culture-negative. Prior respiratory support and surgical conditions were present in 37/53 (70%) and 19/53 (36%) neonates, respectively. Crude mortality was high (20/53; 38%) with no significant difference between culture-confirmed CRE versus clinically suspected culture-negative CRE groups (10/23 [44%] vs 10/30 [33%]; p = 0.45). Hypomagnesaemia (10/38; 26%) and hypokalaemia (15/38; 40%) were frequent; acute kidney injury was rare (1/44; 2%). Three CRE infection clusters were identified by genotypic analysis of 20 available isolates (18 [90%] bla NDM-1 [New Delhi metallo-beta-lactamase], 2 [10%] bla OXA [oxacillinase]-48). Conclusion: Neonates receiving colistin therapy were predominantly preterm, with multiple risk factors for infection. Colistin-associated electrolyte derangement was frequent. Over one-third of neonates died. Bla NDM-1 was the most frequent carbapenemase gene identified in the outbreak isolates. Contribution: Colistin was safely used during an Enterobacterales outbreak in predominantly premature and surgical neonates. The mortality was high.

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Pregnancy in Sub-Saharan Africa: A 6-Country Retrospective Cohort Analysis.

BACKGROUND: Few data are available on COVID-19 outcomes among pregnant women in sub-Saharan Africa (SSA), where high-risk comorbidities are prevalent. We investigated the impact of pregnancy on SARS-CoV-2 infection and of SARS-CoV-2 infection on pregnancy to generate evidence for health policy and clinical practice. METHODS: We conducted a 6-country retrospective cohort study among hospitalized women of childbearing age between 1 March 2020 and 31 March 2021. Exposures were (1) pregnancy and (2) a positive SARS-CoV-2 RT-PCR test. The primary outcome for both analyses was intensive care unit (ICU) admission. Secondary outcomes included supplemental oxygen requirement, mechanical ventilation, adverse birth outcomes, and in-hospital mortality. We used log-binomial regression to estimate the effect between pregnancy and SARS-CoV-2 infection. Factors associated with mortality were evaluated using competing-risk proportional subdistribution hazards models. RESULTS: Our analyses included 1315 hospitalized women: 510 pregnant women with SARS-CoV-2, 403 nonpregnant women with SARS-CoV-2, and 402 pregnant women without SARS-CoV-2 infection. Among women with SARS-CoV-2 infection, pregnancy was associated with increased risk for ICU admission (adjusted risk ratio [aRR]: 2.38; 95% CI: 1.42-4.01), oxygen supplementation (aRR: 1.86; 95% CI: 1.44-2.42), and hazard of in-hospital death (adjusted sub-hazard ratio [aSHR]: 2.00; 95% CI: 1.08-3.70). Among pregnant women, SARS-CoV-2 infection increased the risk of ICU admission (aRR: 2.0; 95% CI: 1.20-3.35), oxygen supplementation (aRR: 1.57; 95% CI: 1.17-2.11), and hazard of in-hospital death (aSHR: 5.03; 95% CI: 1.79-14.13). CONCLUSIONS: Among hospitalized women in SSA, both SARS-CoV-2 infection and pregnancy independently increased risks of ICU admission, oxygen supplementation, and death. These data support international recommendations to prioritize COVID-19 vaccination among pregnant women.