Study design and population
A prospective cross-sectional study of neonates evaluated for suspected bacterial infection was conducted at the Tygerberg Hospital Neonatal Unit, Cape Town, South Africa between 1 February-31 October 2018. Any baby hospitalised on a neonatal ward or in the neonatal intensive care unit (NICU) with 1 or more blood cultures submitted during the study period was eligible for enrolment. The enrolment strategy entailed convenience sampling of eligible neonates on weekdays only, where the baby’s mother was on-site and willing to provide written informed consent to data collection and 30-day follow-up. The Stellenbosch University Health Research Ethics Committee and the Tygerberg Hospital management reviewed and approved the study protocol (N18/07/068).
Tygerberg Hospital is a 1384-bed public teaching hospital. Despite being classified as an upper middle-income country by the World Bank, South Africa has one of the world’s highest Gini coefficients indicating inequality.22 Most patients utilizing the public healthcare service are indigent and more typical of the population from LMIC. In 2017, the antenatal HIV prevalence in the Western Cape Province was 15.9% (95% CI: 14.2%–17.8%), with universal antiretroviral therapy in pregnancy and a national mother-to-child HIV infection transmission rate of 0.9%.23 Tygerberg Hospital’s busy obstetric-neonatal service manages approximately 8000 high-risk deliveries (37% low birth weight rate) and 3000 neonatal admissions annually.
Description of the neonatal unit
The 124-bed neonatal unit includes a 12-bed NICU, three high-dependency wards, and one kangaroo mother care ward, with mean occupancy rates exceeding 100%. The neonatal unit provides medical and surgical care for sick, preterm (<37 weeks’ gestation) and/or low-birthweight (<2500 g) inborn and outborn neonates from surrounding district hospitals and midwife obstetric units. Prematurity, perinatal asphyxia and infection are the most common indications for admission. Critically ill neonates are nursed in the NICU, with availability of respiratory support (conventional ventilation, oscillation and nasal continuous positive airway pressure [nCPAP]), inotropic support and nitric oxide therapy. Given the extreme shortage of NICU beds, non-invasive ventilation (nCPAP and high-flow oxygen therapy) is used extensively on the high-dependency wards. Central lines (umbilical venous catheters and peripherally inserted central catheters) are used in all wards; a central line-associated BSI (CLABSI) prevention programme was launched in the NICU in 2012, and subsequently expanded to 2 other neonatal wards. The hospital’s on-site Unit for Infection Prevention and Control (IPC), has one infection prevention nurse practitioner dedicated to the maternity, paediatric and neonatal departments. The Unit for IPC disseminates monthly surveillance reports on BSI and blood culture contamination rates in the neonatal unit.
Clinical evaluation of suspected neonatal infection
Indications for neonatal infection evaluation at Tygerberg Hospital include: maternal risk factors for infection at birth (e.g. chorioamnionitis, prolonged rupture of membranes, unexplained preterm delivery); and neonatal signs of infection at birth or during hospital stay. These include abnormal vital signs (temperature, glucose, respiratory and/or heart rate), and signs or symptoms suggestive of infection (respiratory distress, apnoea, lethargy, poor feeding, abdominal distention, vomiting). For babies with maternal risk factors at birth, a blood culture and full blood count is collected, with delayed collection of blood for C-reactive protein (CRP) testing at 24-48 hours, with antibiotic discontinuation for well babies with CRP <10mg/dL and where blood culture has not flagged positive. For babies with suspected infection at birth or during hospitalisation, a full blood count, CRP and a single blood culture sample is obtained by peripheral blood draw. CRP is widely used in this unit as an antibiotic stewardship tool to reduce neonatal antibiotic duration, when possible. Additional blood cultures may be obtained through a central line for infants with suspected CLABSI.
Antimicrobial management of neonatal infection
The hospital’s guideline for empiric antibiotic therapy for suspected neonatal infection recommends ampicillin plus gentamicin for early-onset infection (<72 hours of life). For HAI (≥72 hours of life) piperacillin-tazobactam plus amikacin are empirically prescribed for stable neonates, and meropenem for critically ill neonates or neonates with suspected meningitis. For patients with HAI in the presence of thrombophlebitis or recent use of central lines, vancomycin is added at the clinician’s discretion. Antifungal therapy (amphotericin B or fluconazole) is added for selected neonates with risk factors for invasive fungal infection (e.g. abdominal surgery, persistent thrombocytopaenia) at the discretion of the neonatal consultant; the unit does not use routine fluconazole prophylaxis.
Laboratory procedures for blood culture processing
The onsite National Health Laboratory Service uses the automated BacT/Alert blood culture system (BioMerieux, Marcy l’Etoile, France). Local guidelines recommend inoculating at least 1–2 ml of blood into a paediatric blood culture bottle (BacT/ALERT PF bottle). If bacterial growth is detected, a Gram stain is performed and the sample sub-cultured onto appropriate media and incubated overnight. Further identification and antimicrobial susceptibility testing of clinically significant isolates is performed with the automated Vitek II system (BioMerieux) using Clinical and Laboratory Standards Institute (CLSI) breakpoints.24 If urinary tract infection, meningitis or another infection focus is suspected, additional laboratory specimens are submitted.
Data definitions and sources
Patient records and hospital admissions data were utilised to collect data on patient demographics, clinical and antimicrobial management of infection episodes, length of stay and 30-day outcome. Laboratory records were used to collect data on blood investigations, blood culture pathogen identification and antimicrobial susceptibility patterns. Clinical outcome at 30-days after blood culture collection was confirmed by folder review for neonates still hospitalised and telephonically for those that had been discharged or transferred. Caregivers and their neonates who could not be telephonically traced following discharge or transfer were indicated as “lost to follow-up” at the 30-day outcome check.
The following standard definitions were used to stratify neonates: low birthweight (<2500 g), very low birthweight (1000-1500g) and extremely low birthweight (<1000 g). Inborn neonates refers to babies born at Tygerberg Hospital, whereas outborn refers to those born at another hospital, midwife obstetric unit or born before arrival. Prior antibiotic therapy was defined as administration of one/more systemic antibiotic doses (documented in the prescription chart) that occurred prior to the current infection episode. Definitions proposed by Wirtschafer8 were used to classify infection episodes as: proven BSI (blood culture-positive with a pathogen); presumed infection (clinically suspected, blood culture-negative infection, with or without risk factors for infection at birth) and potential infection (clinically well neonate with risk factors for infection at birth).
A BSI episode was defined as a blood culture yielding a pathogen, including repeat cultures isolating the same pathogen within 10 days of the original specimen. HA-BSI were defined as a positive blood culture yielding a known neonatal pathogen (based upon the categorization of the United States Centers for Disease Control, US CDC)25 obtained at ≥72 hours of life/hospitalization. Coagulase-negative staphylococci (CoNs) were classified as pathogens if the same species was isolated from a repeat blood culture from a separate blood draw collected on the same/subsequent day. If a contaminant was isolated, the blood culturing episode was allocated to the potential infection group (if they had infection risk factors only) or the presumed infection group (if they had clinical symptoms/signs of infection, irrespective of risk factors for infection).
BSI-attributable death was defined as occurring within 72 hours of blood collection that established a proven BSI, where the treating clinician considered the neonate’s demise to be a consequence of the BSI and/or its infectious complications.26 Data regarding the patient’s demographic profile, infection episode laboratory results, pathogen and antimicrobial resistance spectrum and 30-day outcome were entered into a REDCap database.27
Antibiotic susceptibility patterns
The following susceptibility patterns were regarded as an antibiotic–resistant phenotype: methicillin resistance in S. aureus; third or fourth generation cephalosporin resistance in E. coli and K. pneumoniae (likely extended-spectrum β-lactamase production - ESBL); fourth generation cephalosporin resistance in E. cloacae and S. marcescens (ESBL or derepressed AmpC), carbapenem resistance in A. baumannii or P. aeruginosa, and azole resistance in Candida species.
Continuous and categorical variables were compared using the Kruskal-Wallis test and the X2 test, respectively. To determine factors associated with mortality from LC-BSI, intelligent multivariable logistic regression analyses were performed. A p-value of <0.05 was considered statistically significant. Stata Statistical Software version 13.0 IC (College Station, TX: StataCorp LP) was used for analysis.