Problem

Microbial resistance to antibiotics is a serious global health problem compounded by antibiotic overuse and limited investment in new antibiotic research. There are specific concerns that inappropriate antibiotic exposure in the perinatal period can lead to both short-term and lifelong adverse outcomes. In contrast, the neonatal population is vulnerable to infection and antibiotics could be lifesaving. The only effective strategy is to rationalise and reduce the inappropriate use of antibiotics. Implementing change in this setting would require strong evidence of benefit that outweighs the risk for the population, the weight of a powerful collaborative to influence a paradigm shift, strong clinical leadership and partnership with families. Our neonatal unit (NNU) was the first in the UK to collaborate in an international quality improvement programme (QIP) with the Vermont Oxford Network (VON) and the Centers for Disease Control and Prevention (CDC) to rationalise and safely reduce antibiotic use. In January 2016, a multidisciplinary team of professionals agreed a SMART aim to reduce antibiotic usage rate (AUR) on the NNU by 20% of baseline by 31st December 2016 without compromising patient safety.

Singleton hospital hosts a 24-bedded NNU in Swansea, the second largest city in Wales. It serves a population of 1 million in South West Wales, a mixture of dense urban and sparsely populated rural areas. The unit provides comprehensive medical intensive care for all newborn infants from 23 weeks gestation onwards. Surgical care is provided at the regional centre in Cardiff. The unit caters for 10 000 births in the region and manages approximately 100 very low birthweight infants a year; 20% of all admissions are out born. The unit employs 125 whole time equivalent staff members. However, the number needed to influence this multidisciplinary team is significantly higher due to part-time working and trainees on rotational placements.

In this paper, we report our experience of developing and managing a QIP on safe reduction of antibiotic usage in a tertiary NNU conforming to the ‘Standards for Quality Improvement Reporting Excellence’ (SQUIRE 2.0) guidelines.1

Background

Microbial resistance to antibiotics has risen rapidly over the last two decades with emergence of super-resistant microbial strains that do not respond to the commonly used antibiotics. Antibiotic use increases the presence of resistance genes in the bacteria and further exposure selects for different sets of resistance leading to development of multidrug resistance organisms (MDROs) in the gut microbiota. Studies confirm a much wider spectrum of antibiotic resistance genes in the gut microbiota of preterm babies who had received antibiotics.2–4 It is probable that MDROs persist in the host microbiome for a lifetime and may even be passed to the next generation. The situation is compounded by limited investment in new antibiotic research; only two antibiotic classes have been introduced in the last 50 years with very few new products in the pipeline.5 New antibiotics will take many years to filter into clinical practice, and until then, the only effective strategy is high-quality antibiotic stewardship.

The magnitude of this serious global health problem is highlighted by the 2014 WHO report, warning of the dangers of a postantibiotic era, in which common infections and minor injuries could be fatal.6 This has prompted calls in the USA and the UK for national action plans to combat antibiotic resistance.7 US President Barack Obama published a white paper that led the CDC to launch a collaborative QIP with VON, the world’s largest neonatal benchmarking organisation.8

NNUs are traditionally at risk of antibiotic overuse. The setting is highly emotive and the perception of risk is high as it concerns a vulnerable and immunologically immature population, exposed to many invasive procedures and with a high incidence of clinical instability, often erroneously attributed to infection. It is common to commence empirical antibiotic treatment. ‘Treat first, think later’ is the custom and practice and can lead to a defensive mindset. Yet, the overall incidence of true blood culture-positive early-onset sepsis is low (0.7–1/1000 live births overall); lower still in the term and near-term infants.9 10 The incidence in babies who are admitted to NNUs is 5.6/1000.11 The majority of infants are treated unnecessarily with antibiotics, and the number needed to prevent one true sepsis is very large. A large retrospective cohort study in 127 NNUs in the USA reported wide variation in AUR. There were no differences in rates of proven sepsis, necrotising enterocolitis (NEC), surgical case volume and mortality between the high and the low prescribing units. The only difference between the units was the rate of suspected clinical sepsis, suggesting an avoidable inappropriate use of antibiotics.12

Of greater concern are reports from many other studies where early use of antibiotics without proven morbidities, especially in the first week of life, is associated with increased risk of subsequent mortality and diseases such as late-onset sepsis, NEC and severe retinopathy of prematurity.13–17 The effect size of these adverse events increased with the duration of early antibiotic use.

There is emerging evidence that administration of antibiotics in early life has profound and lifelong adverse effects. The perinatal period is critical for the establishment of the intestinal microbiome. The ‘sterile womb’ theory, whereby the ‘sterile fetus’ first acquires bacteria by passing through the birth canal, has been recently challenged. Studies suggest that the colonisation of the fetal gut may in fact commence prior to birth by bacterial translocation from the maternal oral cavity and gut via the circulation or ascension from the vagina.18 The infant microbiome modulates the immune system development and produces metabolites, important in ‘cross-talk’ between the two. Antibiotic use in pregnancy and the neonatal period results in altered composition of the microbiome (bacterial dysbiosis). This can potentially disrupt the complex immunological development at a critical stage, leading to chronic inflammation with lifelong sequelae.19 20 Bacterial dysbiosis in early life may thus be linked to disease processes such as inflammatory bowel disease, diabetes mellitus, allergic disease and obesity.21–25

Measurement

Our primary outcome measure was the AUR calculated as the number of days of antibiotic use per 1000 patient-days. We collected these data separately for blood culture-positive and blood culture-negative patients, as well as by antibiotic class. Moreover, we agreed on three process measures:

• The proportion of culture-negative septic screens where antibiotics were stopped appropriately at 36–48 hours=number of culture-negative septic screens where antibiotics were stopped at 36–48 hours × 100/total number of culture-negative septic screens.

• The proportion of infants who never received antibiotics during their entire stay on the NNU=number of infants who never received antibiotics during admission × 100/total number of babies admitted to the NNU.

• Antibiotic usage days per patient at discharge.

The department submitted and analysed outcome data on mortality and common morbidities through VON Nightingale system and Badgernet, a live internet-based electronic database widely used in the NNUs in the UK (Clevermed, Edinburgh, UK). Critical incidents were reported and investigated through the critical incident reporting system (DATIX, London).

In the absence of existing reporting system on antibiotic usage, we agreed and adhered to a written data collection methodology before embarking on the QIP. To ensure reliability of the data source, we triangulated data on antibiotic usage from three independent sources between November 2015 and January 2016:

• Pharmacist-led prescription chart audit.

• Medical review of clinical notes.

• Badgernet electronic portal—daily entry of medications by nurses including antibiotics.

Following a high degree of conformity, Badgernet was the agreed data source for prospective monitoring. Data from November 2015 until January 2016 served as baseline. We excluded routine fluconazole prophylaxis in high-risk preterm infants and trimethoprim for renal conditions from analysis as clinicians were reluctant to change this practice. We used two rotating teams of nurses, doctors and nurse practitioners every three months for data collection and analysis to avoid data fatigue and monotony. We reviewed data every 15 days and reported to the wider team every month, earlier if a trigger threshold was reached. Sequential data over time were presented as run charts and quantitative data at the beginning and end of the QIP analysed using non-parametric statistical tests.

Our baseline measurements showed the following:

• The overall  median AUR was 347/1000 patient-days and 268/1000 patient-days in culture-negative sepsis.

• The proportion of culture-negative sepsis screens where antibiotics were stopped within 36–48 hours was 32.5%.

• The proportion of admitted infants who had no exposure to antibiotics at discharge was 21.9%.

• The median antibiotic days per patient at discharge were 3.

In early February 2016, we participated in a VON day spot audit that benchmarked our NNU’s AUR on the 50th–75th centile when compared with other participating centres across the world.

Design

A multidisciplinary team of professionals (medical and nursing staff, advanced nurse practitioners, pharmacists and administrative staff) and parents joined the QIP collaborative ‘Choosing Antibiotics Wisely’ in December 2015. The programme was officially launched in January 2016. Funding was obtained from the unit’s ‘Training and education charitable fund’ with support and encouragement from senior clinicians, managers and executives. The project was reviewed by the institution’s ‘NHS Research and Development’ department and classed as ‘Quality Improvement’ rather than ‘Research’. The project was therefore exempt from ethical approval and consent process.

The team joined in a series of live webinars organised by VON where world experts presented a balanced analysis of the benefits of antibiotic use in the at-risk neonatal population with the potential harm that inappropriate usage may have on short-term and long-term outcomes. They offered judicious improvement strategies and shared success stories. The webinars included robust sessions on quality improvement methodology. A learning management system offered access to handouts, video recordings of lectures, toolkits and discussion forums. The webinars were followed by local deliberations in academic meetings to agree and implement good practices that suited our own clinical setting. Our primary drivers were enshrined in four basic pillars—to establish a culture of antibiotic stewardship, maintain partnership with staff and families, avoid inappropriate prolongation of antibiotics and introduce consensus guidance to safely reduce initiation of antibiotics in selected low-risk infants. The guidance for non-initiation was balanced by a safety net of enhanced clinical review through repeated physical examinations and laboratory tests undertaken by senior clinicians.

Strategy

Multiple initiatives were undertaken to ensure staff and families were aware and actively involved in the programme (Plan–Do–Study–Act (PDSA) 1). Information about infection and the pros and cons of antibiotic use was disseminated through posters displayed on the unit. Leaflets in the admission pack for parents encouraged them to be present on ward rounds and ask questions about their baby, and specifically about antibiotic use. Such information was mixed with other health promotion messages such as breastfeeding and infection control measures to reduce unnecessary anxiety. Weekly parent education classes (as part of our developing family integrated care programme) further reinforced these messages. Noise-reducing headphones ensured that parents could stay at their baby’s cot side during lengthy ward rounds, while maintaining confidentiality rights of other families on the unit. Signed and dated stickers on prescription charts confirmed that nurses/doctors had communicated information on any new antibiotic prescription to the parents. One highly motivated parent even attended the initial VON webinar. Parents and staff were also reassured by the availability of enhanced early warning systems on the unit such as predictive Heart Rate Characteristics (HRC) monitoring system. Staff and parent awareness audits were built in the programme at different times to assess and heighten awareness.

Once these processes were established, we sequentially introduced a series of further clinical PDSA cycles to reduce antibiotic use:

• PDSA 2 (March 2016): Introduction of stickers on prescription charts to trigger mandatory review of antibiotics at 36 hours, backed up by additional scrutiny on daily pharmacist-led ward rounds.

• PDSA 3 (April 2016): Introduction of non-initiation of antibiotic guideline in low-risk admitted infants>34 weeks (online supplementary appendix 1). This was agreed through a review of risk factors in all cases of culture-positive early-onset sepsis over a 10-year period in our institution. Although the process was tested, the number of babies eligible was too small to make a difference and this led to PDSA 4.

• PDSA 4 (June 2016): Lowering of the gestation limit to >30 weeks for non-initiation of antibiotics supported by biweekly PDSA review. The intervention risk was balanced by repeated clinical reviews, additional laboratory tests and HRC monitoring (online supplementary appendix 1). Data on adverse effects such as delayed treatment leading to harm, death, NEC, late-onset sepsis and mortality were collected through routine incident reporting and data collection tools.

• PDSA 5 (July 2016): Stopping antibiotics earlier than initial predicted course in culture negative well infants, if C-reactive protein (CRP) <10 (online supplementary appendix 2).

Many other initiatives also took place concurrently including specifying the minimum blood volume of 1 mL for blood cultures, expediting transit time to the laboratory, facilitation of 36 hours blood culture reporting, introduction of central line care bundles and family integrated care programme.