The epidemiology, risk factors and diagnosis of neonatal sepsis

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, South Africa 2017.Background: In sub-Saharan Africa, sepsis is the third most common cause of deaths during the neonatal period. Both maternal human immunodeficiency virus (HIV) infection and vitamin D deficiency (VDD) have been identified as risk factors for infection in children. The relationship of these risk factors, especially VDD among neonates in developing countries is not well documented. The “gold” standard to diagnose sepsis is blood culture; however, it has low sensitivity. Therefore there is a need for tests with improved sensitivity, to improve estimates of the incidence and aetiology of neonatal sepsis. This could enable prompt and targeted use of antibiotics to reduce both mortality and mitigate against emergence of antimicrobial resistance. The aims of this study were to determine the epidemiology of early-onset sepsis (EOS) and community acquired sepsis (CAS) using standard blood culture. Further, we evaluated the role of molecular diagnostic using polymerase chain reaction (PCR) based technology (Taqman array card), and evaluated role of maternal HIV infection and vitamin D status as risk factors for EOS and CAS in neonates born in Soweto, South Africa. Methods and Procedures: Neonates born and/ or admitted with a diagnosis of possible serious bacterial infection (pSBI) with no previous hospital admission were prospectively enrolled into the study. They were grouped into EOS (onset of sepsis before 3 days of life) and CAS (onset of sepsis between 3-27 days of life). A subgroup of patients who met a predetermined definition of clinical or culture confirmed neonatal sepsis (protocol-defined sepsis), had blood and naso/oro-pharyngeal (NPOP) swabs tested using a PCR- based technique, Taqman array card (TAC) to identify possible causative pathogens. Healthy neonates were enrolled as controls, matched for age-group of cases with sepsis. In a separate cohort, mother-newborn dyads were enrolled soon after birth, and had blood taken to measure serum 25-hydroxyvitamin D [25(OH)D]. These newborns were grouped as being healthy or ill with sepsis. Sepsis in this cohort was defined as presence of clinical signs together with the presence of a positive blood culture and/or high C-reactive protein or interleukin-6. For both cohorts, cases and controls were stratified according to HIV exposure. Results: There were 34,808 live births in Soweto over the study period, August 2013 to September 2014. A total of 3260 neonates were enrolled, 2624 (80%) and 636 (20%) with a diagnosis of early-onset pSBI (EO-pSBI) and community acquired pSBI (CA-pSBI) respectively. Blood culture positivity rate due to pathogens in neonates with EO-pSBI was 3.7% (96/2624). The incidence (per 1000 live births) of EO-pSBI was 106 (95%CI 102-109 and 3.8 (95% CI 3.2-4.6) for culture-confirmed EOS. More than two thirds of putative pathogens isolated from neonates with culture-confirmed EOS (69.8%) were Gram positive bacteria. The common bacteria were Group B streptococcus (GBS; 35/105; 33%) , Viridans streptococcus (23/105; 22%), Enterococcus species (10/105; 10%) and Escherichia coli (E. coli; 10/105; 10%), with incidences (per 1000 live births) of 1.41 (95%CI 1.06-1.86), 0.92 (95%CI 0.65-1.30), 0.40 (95% CI 0.20-0.61) and 0.40 (95% CI 0.20-0.61) respectively. HIV exposed neonates had higher incidence of sepsis than HIV unexposed for EO-pSBI (OR:1.45; 95%CI 1.34-1.56). The overall case fatality rate was 9.0% (236/2624) for EOS. Blood culture positivity rate due to pathogens in neonates with CA-pSBI was 9% (55/636). The incidence of CA-pSBI and blood/CSF culture confirmed CAS were 33.4 (95%CI 31.6-35.4) and 3.53 (95%CI 2.96-4.22), respectively. More than three-quarters (76.7%) of putative pathogens isolated from CA-pSBI were Gram positive bacteria. Among, the culture-confirmed CAS, common organisms in blood were Viridans streptococci (17/60; 28%), GBS (14/60; 23%), Staphylococcus aureus (12/60; 20%), and E.coli (9/60; 15%); while in CSF the common organisms were GBS (9/25; 36%), Staphylococcus aureus (5/25; 20%), Viridans streptococcus (4/25; 16%) and Enterococcus species (4/25; 16%). The overall incidence for common organisms in blood and/ or CSF for CAS were 0.95 (95%CI 0.67-1.33), 0.90 (95%CI 0.63-1.27), 0.75 (95%CI 0.51-1.10) and 0.58 (95%CI 0.37-0.89) for Staphylococcus aureus, Viridans streptococcus, GBS and Enterococcus species respectively. HIV exposed neonates had higher incidence of blood/CSF culture confirmed CAS than HIV unexposed (OR:1.90;95%CI 1.32-2.74), including specifically for Staphylococcus aureus (OR:2.71; 95% CI 1.35-5.41), GBS (OR:4.82; 95%CI 2.13-10.9) and E.coli (OR:2.71; 95%CI 1.07-6.82). . The case fatality rate for CAS was 1.4% (9/636). Among protocol-defined sepsis cases tested with TAC, bacteria or viruses were detected in blood in 37.1% of cases with EOS. Although similar organisms were identified in blood of cases and controls, proportion of cases with positive TAC was higher than in controls (37.1% vs 19.5%; OR: 2.35; 95%CI 1.72-3.21). The common organisms identified in blood of EOS cases using TAC were Streptococcus pneumoniae (14.2%), Ureaplasma species (9.2%), Pseudomonas species (8.5%) and GBS (7.0%). In pharyngeal swabs there were fewer cases that tested positive with TAC compared to controls (44.1% vs 53.1%; OR:0.69; 95%CI 0.59-0.90), and the common organisms identified in cases were Ureaplasma species (19.9%), Klebsiella pneumoniae (11.9%) and GBS (8.5%). After applying modelling factoring positive blood culture, one was able to attribute aetiology to a specific pathogen for 26.7% of cases using blood culture and TAC, and therefore 73.3% of cases did not have an identifiable aetiology from the pathogens tested in culture or TAC. Among the positive TAC results in blood and pharyngeal swabs the organisms that were found to be attributable to EOS were Ureaplasma species (5.4%, 95% CI 3.6%-5.1%) , GBS (4.8%, 95%CI 4.1%-5.8%), and Viridans streptococcus (4.2%, 95%CI 3.5%-5.1%). There were no differences in number of cases and controls with positive TAC results between HIV exposed and unexposed neonates. In neonates with CAS protocol-defined sepsis cases tested with TAC, bacteria or viruses were detected in blood in 45.8% of cases. Proportion of cases with positive TAC in blood was higher than in controls (45.8% vs 27.4%; OR: 2.24; 95%CI 1.30-3.86). The common organisms identified included Streptococcus pneumoniae (15.7%), GBS (14.5%) and E. coli (8.3%). In pharyngeal swabs there were no differences in numbers with positive TAC results between cases and controls (75.0% vs 70.1%, OR:1.28; 95%CI 0.77-2.12), and the common organisms identified in cases were GBS (28.0%), Klebsiella pneumoniae (24.2%) and at equal rates (13.6%) were E. coli, Ureaplasma species and Streptococcus pneumoniae. Viruses were identified in 40% of cases in the pharyngeal swabs. There were no differences in number of cases and controls with positive TAC results between HIV exposed and unexposed neonates. Maternal and cord blood 25(OH)D levels were 54.7±30.1 and 39.0±21.3 nmol/L respectively, and prevalence of VDD (defined as a 25(OH)D level of <30 nmol/L) among the women and their newborns was 18.8% and 39.8% respectively. There were no significant differences in 25(OH)D levels or VDD between HIV infected and uninfected pregnant women. On multivariate analysis VDD in neonates was not associated with EOS. Conclusions: There is high burden of neonatal sepsis in Soweto, including significant mortality. Based on blood culture, GBS is the most common pathogen causing EOS; Viridans streptococcus and Staphylococcus aureus the most common causes of culture-confirmed CAS. HIV exposure contributes significantly to a higher burden of bacterial sepsis in neonates. Although molecular detection using the TAC assay identified more bacteria organisms than from blood culture, including non-culturable organisms like Ureaplasma species, its use as a diagnostic tool for sepsis warrants further evaluation due to high positivity rates among healthy neonates for many of the targeted organisms in blood and NPOP swabs. Nevertheless, after correcting for positive controls, a combination of blood culture and TAC improved the detection of organisms in neonates with sepsis. In this study, maternal and newborn VDD was not associated with sepsis; however, this warrants further evaluation since this study had a limited number of neonates with culture confirmed disease.LG201

Improving survival rates of newborn infants in South Africa

BACKGROUND:The number, rates and causes of early neonatal deaths in South Africa were not known. Neither had modifiable factors associated with these deaths been previously documented. An audit of live born infants who died in the first week of life in the public service could help in planning strategies to reduce the early neonatal mortality rate. METHODS: The number of live born infants weighing 1000 g or more, the number of these infants who die in the first week of life, the primary and final causes of these deaths, and the modifiable factors associated with them were collected over four years from 102 sites in South Africa as part of the Perinatal Problem Identification Programme. RESULTS: The rate of death in the first week of life for infants weighing 1000 g or more was unacceptably high (8.7/1000), especially in rural areas (10.42/1000). Intrapartum hypoxia and preterm delivery are the main causes of death. Common modifiable factors included inadequate staffing and facilities, poor care in labour, poor neonatal resuscitation and basic care, and difficulties for patients in accessing health care. CONCLUSION: Practical, affordable and effective steps can be taken to reduce the number of infants who die in the first week of life in South Africa. These could also be implemented in other under resourced countries

Intrapartum asphyxia and hypoxic ischaemic encephalopathy in a public hospital: Incidence and predictors of poor outcome

Objective. To determine the incidence of asphyxia and hypoxic ischaemic encephalopathy (HIE) and predictors of poor outcome in a hospital in a developing country.Methods. Neonates of birth weight ≥2 000 g who required bag-and-mask ventilation and were admitted with a primary diagnosis of asphyxia from January to December 2011 were included. Medical records were retrieved and maternal and infant data collected and analysed. Infants who had severe HIE and/or died were compared with those who survived to hospital discharge with no or mild to moderate HIE.Results. There were 21 086 liveborn infants with a birth weight of ≥2 000 g over the study period. The incidence of asphyxia ranged from 8.7 to 15.2/1 000 live births and that of HIE from 8.5 to 13.3/1 000, based on the definition of asphyxia used. In 60% of patients with HIE it was moderate to severe. The overall mortality rate was 7.8%. The mortality rate in infants with moderate and severe HIE was 7.1% and 62.5%, respectively. The odds of severe HIE and/or death were high if the Apgar score was &lt;5 at 10 minutes (odds ratio (OR) 19.1; 95% confidence interval (CI) 5.7 - 66.9) and if there was no spontaneous respiration at 20 minutes (OR 27.2; 95% CI 6.9 - 117.4), a need for adrenaline (OR 81.2; 95% CI 13.2 - 647.7) and a pH of &lt;7 (OR 5.33; 95% CI 1.31 - 25.16). Predictors of poor outcome were Apgar score at 10 minutes (p=0.004), need for adrenaline (p=0.034) and low serum bicarbonate (p=0.028).Conclusion. The incidence of asphyxia in term and near-term infants is higher than that reported in developed countries. Apgar score at 10 minutes and need for adrenaline remain important factors in predicting poor outcome in infants with asphyxia

Incidence and All-Cause Mortality Rates in Neonates Infected With Carbapenem Resistant Organisms

INTRODUCTION: Multidrug-resistant, Gram-negative infections, particularly due to carbapenem resistant organisms (CRO), have increased globally. Few studies have reported on the burden of CRO in neonates from low-middle income countries (LMIC). This study aimed to determine the incidence and mortality rates of culture-confirmed Gram-negative infections, with a special focus on CRO in a neonatal unit from a LMIC. MATERIALS AND METHODS: Positive bacterial cultures from sterile sites of infants admitted in the neonatal unit from the 1st January 2018 to 31st December 2019, were reviewed retrospectively. Type of organism, susceptibility and outcomes were recorded. Data on Gram-negative isolates, including the CRO, were extracted. Rates and outcomes were analysed. RESULTS: There were 2219 neonates with organisms isolated from sterile sites (blood and cerebrospinal fluid), accounting for 30% of all admissions, giving a neonatal sepsis incidence of 17.9/1000 patient-days. There was a total of 1746 positive isolates (excluding coagulase negative Staphyloccocus). Of these, 1706 (98%) were isolated from blood, and 40 (2%) from cerebrospinal fluid. Overall, 1188 (68%) were Gram-negative, 371 (21%) Gram-positive and 187 (10.7%) fungal isolates. The common Gram-negatives were Acinetobacter baumannii (526/1188;44%) and Klebsiella pneumoniae (469/1188;40%). Carbapenem resistance was observed in 359 (68%) of the Acinetobacter baumannii (CRAB) and in 103 (18%) of the Enterobacterales (CRE) isolates, with 98% of CRE being Klebsiella pneumoniae (CR-Klebs). Twenty-four (41%) of Pseudomonas species were carbapenem resistant. Overall, carbapenem resistance was seen in 42% of all Gram-negative organisms. The rate of CRAB and CRE were 2.9 and 0.8/1000 patient-days respectively. The overall, all-cause in-hospital mortality rate in infants with Gram-negative isolates was 22%, with higher mortality rate in those infected with CRO compared to non-CRO (34% vs 13%; OR 3.44; 95% CI 2.58–4.60; p < 0.001). The mortality rate in infants with CRE was higher than those with CRAB (48% vs 33%; OR 1.85; 95% CI 1.18–2.89; p = 0.007). CONCLUSION: We observed a high incidence of positive cultures from sterile sites. The common organisms isolated were Gram-negatives, and among these carbapenem resistance was high and was associated with high mortality. Mortality was higher in infants with CRE compared to those with CRAB

Frequent Genital HSV-2 Shedding among Women during Labor in Soweto, South Africa

Background. Despite high herpes simplex virus type 2 (HSV-2) incidence and prevalence among women in Africa, we are unaware of published neonatal herpes reports. To assess neonatal HSV transmission potential in South Africa, we investigated the frequency of the strongest risk factors: HSV acquisition in late pregnancy and HSV shedding during labor. Methods. Women admitted in early labor to a hospital in Soweto underwent HSV serologic testing and genital swab collection for HSV PCR. HSV-2 seronegative women were assessed for seroconversion 4–6 weeks after delivery. Results. Of 390 women enrolled, 229 (58.7%) were HSV-2 seropositive. Genital HSV-2 was detected in 17.2% of HSV-2 seropositive women, including 26 of 115 HIV-positive and 13 of 110 HIV-negative women (22.6% versus 11.8%; RR, 1.91; 95% CI, 1.04–3.53; P=0.038), but in none of 161 HSV-2 seronegative women. Among the 91 HSV-2 seronegative women followed after delivery, none seroconverted. Conclusions. HSV-2 reactivation is common among South African women during labor, especially those with HIV coinfection. To determine the epidemiology of neonatal herpes in South Africa and to investigate whether the lack of reported cases is due to alterations in immune control or HSV-2 virulence, studies evaluating acutely ill neonates for HSV and studies of maternal HSV-2 shedding patterns are needed

Therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy should not be discontinued in low- and middle-income countries

Perinatal asphyxia is a major cause of death and disability in children. Therapeutic hypothermia (TH) has become a standard of care for newborn infants who have sustained hypoxic ischaemic encephalopathy (HIE) due to perinatal asphyxia. There is compelling evidence to support this approach. A Cochrane systematic review of 11 prospective randomised controlled trials including 1 505 newborns showed that TH started within 6 hours of birth in infants with HIE significantly decreased mortality and neurodevelopmental disability in survivors.http://www.samj.org.zadm2022ImmunologyPaediatrics and Child Healt

COVID-19 preparedness—a survey among neonatal care providers in low- and middle-income countries

Objective - To evaluate COVID-19 pandemic preparedness, available resources, and guidelines for neonatal care delivery among neonatal health care providers in low- and middle-income countries (LMICs) across all continents. Study design - Cross-sectional, web-based survey administered between May and June, 2020. Results - Of 189 invited participants in 69 LMICs, we received 145 (77%) responses from 58 (84%) countries. The pandemic provides significant challenges to neonatal care, particularly in low-income countries. Respondents noted exacerbations of preexisting shortages in staffing, equipment, and isolation capabilities. In Sub-Saharan Africa, 9/35 (26%) respondents noted increased mortality in non-COVID-19-infected infants. Clinical practices on cord clamping, isolation, and breastfeeding varied widely, often not in line with World Health Organization guidelines. Most respondents noted family access restrictions, and limited shared decision-making. Conclusions - Many LMICs face an exacerbation of preexisting resource challenges for neonatal care during the pandemic. Variable approaches to care delivery and deviations from guidelines provide opportunities for international collaborative improvement

International train the trainer neonatal antibiotic stewardship program for South African pharmacists

Hospital-acquired antimicrobial-resistant infections are a leading cause of neonatal mortality in South African (SA) neonatal intensive care units (NICU). There is an urgent need for NICU Antibiotic Stewardship Programs (ASP). We describe the development of an international Train-the-Trainer (TTT) NICU-ASP mentoring program for SA pharmacists. A partnership between the South Africa Antimicrobial Stewardship in 2019. A baseline assessment of four SA NICUs was done to guide the development of a TTT NICU-ASP mentoring of SA pharmacists utilizing the existing workforce. The program included bilateral site visits. Pre-post surveys were used to assess SA mentee's NICU experiences, barriers to clinical pharmacy services and confidence to train additional pharmacists in NICU ASP. Four mentees from private (n = 1) and public hospitals (n = 3) completed a 2-week TTT NICU-ASP in the US that included; education, patient care rounds, role-playing, peer-to-peer sessions and behavioral interventions followed by ongoing support and mentoring by SAASP mentors. None of the hospitals had pharmacists participating in daily patient care rounds or had multidisciplinary NICU-ASPs due to lack of NICU trained pharmacists and dedicated time for ASP. Post surveys showed improved confidence to train additional pharmacists in NICU-ASP. Subsequently, these SA mentees provided NICU-ASP education to over 700 health care professionals and trained six additional pharmacists in NICU-ASP. Mentors and mentees developed a comprehensive NICU ASP toolkit for ongoing training of additional pharmacists. A new research collaboration between TTT NICUASP mentors, mentees and physician members of the South Africa National Neonatal Sepsis Task Force has formed and the first national NICU-ASP study is underway in 12 hospitals. Shared leadership between U.S. and SA mentors led to developing a TTT NICU-ASP for pharmacists tailored to existing resources and local needs.Merck; Pfizer; Bill and Melinda Gates Foundation grant.http://wileyonlinelibrary.com/journal/jac5am2022Pharmacolog