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.

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.

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.

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.

Intensive care unit nurses' knowledge, attitudes and practices of COVID-19 infection prevention and control.

Background: Intensive care units (ICUs) had to rapidly adapt infection prevention and control (IPC) practices during the coronavirus disease 2019 (COVID-19) pandemic. Objectives: To determine ICU nurses' COVID-19 IPC-related knowledge, attitudes, practices, and perceptions. Method: A mixed-methods study was conducted at the Groote Schuur Hospital ICU, Cape Town, South Africa (20 April 2021 and 30 May 2021). Participants completed anonymous, self-administered, knowledge, attitudes and practices (KAP) questionnaires. Individual interviews were conducted regarding nurses' lived experiences and perceptions of COVID-19 IPC in critical care. Results: In total, 116 ICU nurses participated (93.5% response rate) including 57 professional nurses (49%), 34 enrolled nurses (29%) and 25 enrolled nursing assistants (22%); young females (31-49 years) predominating (n = 99; 85.3%). Nurses' overall COVID-19 IPC knowledge scores were moderately good (78%); professional nurses had greater knowledge of COVID-19 transmission (p < 0.001). Intensive care unit nurses' attitude scores towards COVID-19 IPC were low (55%), influenced by limited IPC training, insufficient time to implement IPC and shortages of personal protective equipment (PPE). Respondents' scores for self-reported COVID-19 IPC practices were moderate (65%); highest compliance rates were for hand hygiene after touching patient surroundings (68%). Only 47% ICU nurses underwent N95 respirator fit-testing despite working in a COVID-19 ICU. Conclusion: Regular COVID-19 IPC training is needed to equip ICU nurses with the knowledge and skills to prevent healthcare-associated COVID-19 transmission. Enhanced IPC training and consistent PPE availability may support more favourable attitudes and better IPC practices. Comprehensive IPC and occupational health support should be offered to ensure ICU nurses' wellbeing during pandemics. Contribution: Enhanced IPC training and consistent PPE availability may support better attitudes and IPC practices.

Mortality associated with third-generation cephalosporin resistance in Enterobacterales bloodstream infections at eight sub-Saharan African hospitals (MBIRA): a prospective cohort study.

BACKGROUND: Bacteria of the order Enterobacterales are common pathogens causing bloodstream infections in sub-Saharan Africa and are frequently resistant to third-generation cephalosporin antibiotics. Although third-generation cephalosporin resistance is believed to lead to adverse outcomes, this relationship is difficult to quantify and has rarely been studied in this region. We aimed to measure the effects associated with resistance to third-generation cephalosporins in hospitalised patients with Enterobacterales bloodstream infection in Africa. METHODS: We conducted a prospective, matched, parallel cohort study at eight hospitals across sub-Saharan Africa. We recruited consecutive patients of all age groups with laboratory-confirmed Enterobacterales bloodstream infection and matched them to at least one patient without bloodstream infection on the basis of age group, hospital ward, and admission date. Date of infection onset (and enrolment) was defined as the day of blood sample collection for culturing. Patients infected with bacteria with a cefotaxime minimum inhibitory concentration of 1 mg/L or lower were included in the third-generation cephalosporin-susceptible (3GC-S) cohort, and the remainder were included in the third-generation cephalosporin-resistant (3GC-R) cohort. The primary outcomes were in-hospital death and death within 30 days of enrolment. We used adjusted multivariable regression models to first compare patients with bloodstream infection against matched patients within the 3GC-S and 3GC-R cohorts, then compared estimates between cohorts. FINDINGS: Between Nov 1, 2020, and Jan 31, 2022, we recruited 878 patients with Enterobacterales bloodstream infection (221 [25·2%] to the 3GC-S cohort and 657 [74·8%] to the 3GC-R cohort) and 1634 matched patients (420 [25·7%] and 1214 [74·3%], respectively). 502 (57·2%) bloodstream infections occurred in neonates and infants (age 0-364 days). Klebsiella pneumoniae (393 [44·8%] infections) and Escherichia coli (224 [25·5%] infections) were the most common Enterobacterales species identified. The proportion of patients who died in hospital was higher in patients with bloodstream infection than in matched controls in the 3GC-S cohort (62 [28·1%] of 221 vs 22 [5·2%] of 420; cause-specific hazard ratio 6·79 [95% CI 4·06-11·37] from Cox model) and the 3GC-R cohort (244 [37·1%] of 657 vs 115 [9·5%] of 1214; 5·01 [3·96-6·32]). The ratio of these cause-specific hazard ratios showed no significant difference in risk of in-hospital death in the 3GC-R cohort versus the 3GC-S cohort (0·74 [0·42-1·30]). The ratio of relative risk of death within 30 days (0·82 [95% CI 0·53-1·27]) also indicated no difference between the cohorts. INTERPRETATION: Patients with bloodstream infections with Enterobacterales bacteria either resistant or susceptible to third-generation cephalosporins had increased mortality compared with uninfected matched patients, with no differential effect related to third-generation cephalosporin-resistance status. However, this finding does not account for time to appropriate antibiotic treatment, which remains clinically important to optimise. Measures to prevent transmission of Enterobacterales could reduce bloodstream infection-associated mortality from both drug-resistant and drug-susceptible bacterial strains in Africa. FUNDING: Bill & Melinda Gates Foundation.

Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS).

BACKGROUND: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. METHODS AND FINDINGS: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. CONCLUSION: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03721302).

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

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

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole-resistant Candida spp. isolates in low- and middle-income countries (LMICs) compared to high-income countries (HICs). We describe the epidemiology, Candida spp. distribution, treatment, and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalized infants <60 days postnatal age with sepsis (August 2018-February 2021). A total of 127 neonates from 14 hospitals in 8 countries with Candida spp. isolated from blood culture were included. Median gestational age of affected neonates was 30 weeks (IQR: 28-34), and median birth weight was 1270 gr (interquartile range [IQR]: 990-1692). Only a minority had high-risk criteria, such as being born <28 weeks, 19% (24/127), or birth weight <1000 gr, 27% (34/127). The most common Candida species were C. albicans (n = 45, 35%), C. parapsilosis (n = 38, 30%), and Candida auris (n = 18, 14%). The majority of C. albicans isolates were fluconazole susceptible, whereas 59% of C. parapsilosis isolates were fluconazole-resistant. Amphotericin B was the most common antifungal used [74% (78/105)], followed by fluconazole [22% (23/105)]. Death by day 28 post-enrollment was 22% (28/127). To our knowledge, this is the largest multi-country cohort of NIC in LMICs. Most of the neonates would not have been considered at high risk for NIC in HICs. A substantial proportion of isolates was resistant to first choice fluconazole. Understanding the burden of NIC in LMIC is essential to guide future research and treatment guidelines.

Our study describes neonates from low- and middle-income countries with neonatal invasive candidiasis (NIC). Most of them were outside the groups considered at high risk for NIC described in high-income countries. Candida spp. epidemiology was also different. The mortality was high (22%). Further research in these settings is required.

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.

Circumstances for treatment and control of invasive Enterobacterales infections in eight hospitals across sub-Saharan Africa: a cross-sectional study.

Background: Bloodstream infections caused by Enterobacterales show high frequency of antimicrobial resistance (AMR) in many Low- and Middle-Income Countries. We aimed to describe the variation in circumstances for management of such resistant infections in a group of African public-sector hospitals participating in a major research study. Methods: We gathered data from eight hospitals across sub-Saharan Africa to describe hospital services, infection prevention and antibiotic stewardship activities, using two WHO-generated tools. We collected monthly cross-sectional data on availability of antibiotics in the hospital pharmacies for bloodstream infections caused by Enterobacterales. We compared the availability of these antibiotics to actual patient-level use of antibiotics in confirmed Enterobacterales bloodstream infections (BSI). Results: Hospital circumstances for institutional management of resistant BSI varied markedly. This included self-evaluated infection prevention level (WHO-IPCAF score: median 428, range 155 to 687.5) and antibiotic stewardship activities (WHO stewardship toolkit questions: median 14.5, range 2 to 23). These results did not correlate with national income levels. Across all sites, ceftriaxone and ciprofloxacin were the most consistently available antibiotic agents, followed by amoxicillin, co-amoxiclav, gentamicin and co-trimoxazole. There was substantial variation in the availability of some antibiotics, especially carbapenems, amikacin and piperacillin-tazobactam with degree of access linked to national income level. Investigators described out-of-pocket payments for access to additional antibiotics at 7/8 sites. The in-pharmacy availability of antibiotics correlated well with actual use of antibiotics for treating BSI patients. Conclusions: There was wide variation between these African hospitals for a range of important circumstances relating to treatment and control of severe bacterial infections, though these did not all correspond to national income level. For most antibiotics, patient-level use reflected in-hospital drug availability, suggesting external antibiotics supply was infrequent. Antimicrobial resistant bacterial infections could plausibly show different clinical impacts across sub-Saharan Africa due to this contextual variation.

Impact of a multi-strain probiotic administration on peri-rectal colonization with drug-resistant Gram-negative bacteria in preterm neonates.

Background: Infections caused by drug resistant Gram-negative bacteria (DR-GNB) are a major health concern for hospitalized preterm neonates, globally. The aim of this study was to investigate the effect of a multi-strain probiotic on the incidence of rectal colonization with DR-GNB in preterm neonates. Methods: A double-blind, placebo-controlled, randomized clinical trial was conducted including 200 neonates, randomly allocated to a multi-strain probiotic (n = 100) or placebo (n = 100). Results: Fifteen percent of the neonates showed peri-rectal colonization with DR-GNB on the day of enrolment indicating probable maternal-to-neonate (vertical) bacterial transmission or environmental acquisition at time of delivery, with no difference between groups. Acquisition of further DR-GNB colonization was rapid, with an increase from 15% on the day enrolment to 77% by day 7 and 83% by day 14 of life. By day 7 (corresponding to early gut colonization), neonates in the probiotic group were 57% less likely to have peri-rectal DR-GNB colonization [OR: 0.43 (0.20-0.95); p = 0.04] and by day 14 (corresponding to late gut colonization), neonates in the probiotic group were 93% less likely to have peri-rectal DR-GNB colonization [OR: 0.07 (0.02-0.23); p < 0.001]. Conclusion: Hospitalized neonates showed substantial peri-rectal colonization with DR-GNB at enrolment and further rapid acquisition of DR-GNB in the first 2 weeks of life. The use of a multi-strain probiotic was effective in reducing early and late neonatal gut colonization with DR-GNB. Clinical Trial Registration: The trial was registered at the Pan African Clinical Trial Registry (PACTR202011513390736).

Implementation of infection prevention and control for hospitalized neonates: A narrative review.

BACKGROUND: The most prevalent infections encountered in neonatal care are healthcare-associated infections. The majority of healthcare-associated infections are considered preventable with evidence-based infection prevention and control (IPC) practices. However, substantial knowledge gaps exist in IPC implementation in neonatal care. Furthermore, the knowledge of factors which facilitate or challenge the uptake and sustainment of IPC programmes in neonatal units is limited. The integration of implementation science approaches in IPC programmes in neonatal care aims to address these problems. OBJECTIVES: The aim of this narrative review was to identify determinants which have been reported to influence the implementation of IPC programmes and best practices in inpatient neonatal care settings. SOURCES: A literature search was conducted in PubMed, MEDLINE (Medical Literature Analysis and Retrieval System Online) and CINAHL (Cumulative Index to Nursing and Allied Health Literature) in May 2022. Primary study reports published in English, French, German, Spanish, Portuguese, Italian, Danish, Swedish or Norwegian since 2000 were eligible for inclusion. Included studies focused on IPC practices in inpatient neonatal care settings and reported determinants which influenced implementation processes. CONTENT: The Consolidated Framework for Implementation Research was used to identify and cluster reported determinants to the implementation of IPC practices and programmes in neonatal care. Most studies reported challenges and facilitators at the organizational level as particularly relevant to implementation processes. The commonly reported determinants included staffing levels, work- and caseloads, as well as aspects of organizational culture such as communication and leadership. IMPLICATIONS: The presented knowledge about factors influencing neonatal IPC can support the design, implementation, and evaluation of IPC practices.

Healthcare-associated Infections in Very Low Birth-weight Infants in a South African Neonatal Unit: Disease Burden, Associated Factors and Short-term Outcomes.

BACKGROUND: Infection is a leading cause of death among very low birth-weight (VLBW) infants in resource-limited settings. METHODS: We performed a retrospective review of healthcare-associated infection (HAI) episodes among VLBW infants from January 1, 2016, to December 31, 2017. The epidemiology, causative organisms and short-term outcomes were analyzed. Logistic regression was used to investigate for factors associated with development of HAI. RESULTS: During the study period, 715 VLBW infants with suspected HAI were investigated, including 162/715 (22.7%) proven and 158/715 (22.1%) presumed HAI. Of the proven infections, 99/162 (61.1%) contained at least one Gram-negative organism per blood culture; 84/162 (51.9%) single Gram-negative organisms and 15/162 (9.3%) polymicrobial growth. Independent factors associated with development of any HAI included low gestational age, small for gestational age, indwelling central venous catheter and invasive ventilation. Compared with infants in whom HAI had been excluded, infants with HAI were more likely to be diagnosed with necrotizing enterocolitis (5.6% vs. 23.1%; P < 0.001) and bronchopulmonary dysplasia (1.0% vs. 4.4%; P = 0.007). Infants with any HAI also had a longer hospital stay [44 (25-65) vs. 38 (26-53) days; P < 0.001] and increased mortality [90/320 (28.1%) vs. 21/395 (5.3%); P < 0.001] compared with infants who did not develop HAI episodes. CONCLUSIONS: Proven and presumed HAI are a major contributor to neonatal morbidity and mortality; further research is urgently needed to better understand potential targets for prevention and treatment of HAI in resource-limited neonatal units.

Evaluating the appropriateness of laboratory testing and antimicrobial use in South African children hospitalized for community-acquired infections.

INTRODUCTION: Community acquired infection (CAI) is the leading indication for paediatric hospitalization in South Africa. METHODS: We conducted secondary data analysis of prospective, consecutive paediatric admissions to Tygerberg Hospital (May 2015-November 2015). Clinical characteristics, admission diagnosis, appropriateness of diagnostic tests, use of antimicrobial prescriptions, hospital outcome and costs were analyzed. RESULTS: CAI episodes were documented in (364/451; 81%) children admitted to the general paediatric ward; median age 4.8 months (Interquartile range, IQR, 1.5-17.5) and weight 5.4kg (IQR, 3.6-9.0). Male gender predominated (210/364; 58%), and Human Immunodeficiency Virus infection prevalence was 6.0% (22/364). Common CAI types included respiratory tract infections (197; 54%), gastroenteritis (51; 14%), and bloodstream infections (33; 9%). Pre-hospital antibiotics (ceftriaxone) were given to 152/364 (42%). Of 274 blood cultures and 140 cerebrospinal fluid samples submitted, 5% and 2% respectively yielded a pathogen. Common CAI antibiotic treatment regimens included: ampicillin alone (53%); ampicillin plus gentamicin (25%) and ampicillin plus cefotaxime (20%). Respiratory syncytial virus (RSV) was found in 39% of the children investigated for pneumonia. Most antibiotic prescriptions (323/364; 89%) complied with national guidelines and were appropriately adjusted based on the patient's clinical condition and laboratory findings. The overall estimated cost of CAI episode management ZAR 22,535 (≈1423 USD) per CAI admission episode. Unfavourable outcomes were uncommon (1% died, 4% required re-admission within 30 days of discharge). CONCLUSION: CAI is the most frequent reason for hospitalization and drives antimicrobial use. Improved diagnostic stewardship is needed to prevent inappropriate antimicrobial prescriptions. Clinical outcome of paediatric CAI episodes was generally favourable.

Healthcare-Associated Infection Prevention Interventions for Neonates in Resource-Limited Settings.

Healthcare-associated infections (HAIs) and antimicrobial-resistant (AMR) infections are leading causes of neonatal morbidity and mortality, contributing to an extended hospital stay and increased healthcare costs. Although the burden and impact of HAI/AMR in resource-limited neonatal units are substantial, there are few HAI/AMR prevention studies in these settings. We reviewed the mechanism of action and evidence supporting HAI/AMR prevention interventions, including care bundles, for hospitalized neonates in low- and middle-income countries (LMIC).

Culture-confirmed neonatal bloodstream infections and meningitis in South Africa, 2014-19: a cross-sectional study.

BACKGROUND: Few population-level estimates of invasive neonatal infections have been reported from sub-Saharan Africa. We estimated the national incidence risk, aetiology, and pathogen antimicrobial susceptibility for culture-confirmed neonatal bloodstream infections and meningitis in South Africa. METHODS: We conducted a cross-sectional study of neonates (<28 days of life) admitted to neonatal or paediatric wards of 256 public sector health facilities in South Africa during 2014-19. Diagnostic pathology records from Jan 1, 2014, to Dec 31, 2019, were extracted from a national pathology data warehouse. A case was defined as a neonate with at least one positive blood or cerebrospinal fluid culture during a 14-day period. Incidence risk was calculated using annual numbers of registered livebirths. Among the causative pathogens identified, we calculated the proportion of cases attributed to each of them, as well as the rates of antibiotic susceptibility of Gram-positive and Gram-negative bacteria. FINDINGS: Among 43 438 records of positive cultures, there were 37 631 incident cases of neonatal infection with at least one pathogen isolated. The overall incidence risk of culture-confirmed infections was 6·0 per 1000 livebirths (95% CI 6·0-6·1). The incidence risk of late-onset sepsis (days 3-27 of life) was 4·9 per 1000 livebirths (4·9-5·0) and that of early-onset sepsis (days 0-2 of life) was 1·1 per 1000 livebirths (1·1-1·1); risk ratio 4·4 (95% CI 4·3-4·5). The cause of infection differed by syndrome, timing of infection onset, facility, and province, although Klebsiella pneumoniae (26%), Acinetobacter baumannii (13%), and Staphylococcus aureus (12%) were the dominant pathogens overall. Gram-negative bacteria had declining susceptibility to most antibiotics over the study period. INTERPRETATION: We found a high incidence risk of late-onset sepsis with provincial variations, predominance of K pneumoniae, and declining antibiotic susceptibility among Gram-negative bacteria. This national surveillance in an upper-middle-income country provides a baseline burden of neonatal infections against which the impact of future clinical and public health interventions can be measured. FUNDING: Bill & Melinda Gates Foundation.

SARS-CoV-2 in children and their accompanying caregivers: Implications for testing strategies in resource limited hospitals.

Background: Identification of SARS-CoV-2 infected individuals is imperative to prevent hospital transmission, but symptom-based screening may fail to identify asymptomatic/mildly symptomatic infectious children and their caregivers. Methods: A COVID-19 period prevalence study was conducted between 13 and 26 August 2020 at Tygerberg Hospital, testing all children and their accompanying asymptomatic caregivers after initial symptom screening. One nasopharyngeal swab was submitted for SARS-CoV-2 using real-time reverse-transcription polymerase chain reaction (rRT-PCR). An additional Respiratory Viral 16-multiplex rRT-PCR test was simultaneously done in children presenting with symptoms compatible with possible SARS-CoV-2 infection. Results: SARS-Co-V 2 RT-PCR tests from 196 children and 116 caregivers were included in the analysis. The SARS-CoV-2 period prevalence in children was 5.6% (11/196) versus 15.5% (18/116) in asymptomatic caregivers (p<0.01). Presenting symptoms did not correlate with SARS-CoV-2 test positivity; children without typical symptoms of SARS-CoV-2 were more likely to be positive than those with typical symptoms (10.2% [10/99] vs 1% [1/97]; p<0.01). Children with typical symptoms (97/196; 49.5%) mainly presented with acute respiratory (68/97; 70.1%), fever (17/97; 17.5%), or gastro-intestinal complaints (12/97; 12.4%); Human Rhinovirus (23/81; 28.4%) and Respiratory Syncytial Virus (18/81; 22.2%) were frequently identified in this group. Children-caregiver pairs' SARS-CoV-2 tests were discordant in 83.3%; 15/18 infected caregivers' children tested negative. Symptom-based COVID-19 screening alone would have missed 90% of the positive children and 100% of asymptomatic but positive caregivers. Conclusion: Given the poor correlation between SARS-CoV-2 symptoms and RT-PCR test positivity, universal testing of children and their accompanying caregivers should be considered for emergency and inpatient paediatric admissions during high COVID-19 community transmission periods. Universal PPE and optimising ventilation is likely the most effective way to control transmission of respiratory viral infections, including SARS-CoV-2, where universal testing is not feasible. In these settings, repeated point prevalence studies may be useful to inform local testing and cohorting strategies.