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Abstract
Objective To evaluate the implementation of switch from intravenous-to-oral antibiotic therapy with amoxicillin in neonates with early-onset infection (EOI).
Design, setting and patients A population-based multicentre cohort study. All term-born neonates with EOI were prospectively included between 1 December 2018 to 30 November 2020.
Intervention Intravenous-to-oral switch antibiotic therapy in clinically stable neonates.
Main outcome measures The primary outcome was readmission due to infection. Secondary outcomes were days of hospitalisation and antibiotic use in the pre-implementation versus post implementation period.
Results During 2 years, 835 neonates commenced antibiotics for EOI (1.5% (95% CI 1.4% to 1.6%)) of all term live births). Of those, 554 (66%) underwent a full course of treatment. There were 23 episodes of culture-proven infection (0.42 per 1000 term live births (95% CI 0.27 to 0.63)). A total of 478 of 531 (90%) neonates with probable infection underwent switch therapy. None was readmitted due to infection. The median duration of hospitalisation was 3.0 days (IQR 2.5–3.5) and 7.4 days (IQR 7.0–7.5) in the switch and intravenous therapy groups, respectively. According to antibiotic surveillance data, 1.2% underwent a full course of treatment following implementation of oral switch therapy (2019–2020), compared with 1.2% before (2017–2018).
Conclusion In clinical practice, switch therapy was safe and used in 9 of 10 neonates with probable EOI. Knowledge of the safety of antibiotic de-escalation is important as home-based oral therapy ameliorates the treatment burden for neonates, caregivers and healthcare systems. Despite the ease of oral administration, implementation of switch therapy did not increase the overall use of antibiotics.
- Neonatology
- Infectious Disease Medicine
- Sepsis
- Infant Welfare
Data availability statement
Data are available upon reasonable request. Researchers who provide a methodologically sound proposal will be granted access to a full copy of individual deidentified data. The data will be available from 3 months after the publication of the study, ending 5 years after publication. Proposals should be directed to the corresponding author of this article, and access can be granted after the proposal is approved by the trial steering committee.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Switch from intravenous-to-oral antibiotic therapy in term-born neonates with probable early-onset infection (EOI) has been evaluated to be safe in one randomised controlled trial in a high-income country but has never been evaluated in a ‘real-life’ clinical setting.
WHAT THIS STUDY ADDS
In this prospective cohort study, 90% of eligible neonates underwent oral switch therapy. There was no readmission due to infection among 478 neonates with probable infection. The median hospitalisation was reduced from 7 days to 3 days. The population-based use of antibiotics did not increase after switch therapy was implemented.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Switch from intravenous-to-oral antibiotic therapy in clinically stable term-born neonates with probable EOI was safe and enabled earlier discharge to home. The results support the standard use of intravenous-to-oral switch therapy in neonates with probable EOI.
Introduction
Early-onset bacterial infection is one of the most common causes of hospitalisation for term-born neonates.1 Intravenous antibiotic therapy is initiated on a low suspicion due to non-specific initial symptoms, risk of rapid clinical deterioration, and high morbidity and mortality.2 3 In 60%–75% of cases, early-onset infection (EOI) is rejected, and antibiotics are discontinued after 48 hours.4–6 Neonates with probable or proven EOI receive a full course of antibiotics. Treatment duration in probable EOI varies between countries but is usually 5–7 days. In proven EOI, it depends on the causative agent and can be up to 14 days.7 The current practice is to administer antibiotics intravenously for the entire period.4–6 8 However, intravenous therapy has disadvantages, including the need for hospitalisation and intravenous peripheral catheter reinsertions.9–11 There is emerging evidence to support the effectiveness and safety of switch from intravenous-to-oral administration of antibiotic therapy in neonates with EOI.12–18
Switching from intravenous-to-oral therapy in neonates with EOI has not been evaluated in ‘real-life’ clinical practice. Since findings from clinical trials cannot always be generalised to the population at large due to their stringent eligibility criteria and highly controlled settings, real-life evidence studies complement randomised trials.19 20 In 2018, intravenous-to-oral switch therapy was implemented as routine practice in neonates with EOI in eastern Denmark. In this prospective multicentre, real-life cohort study, we aimed to estimate the risk of readmission due to infection following intravenous-to-oral switch therapy, the duration of hospitalisation and the antibiotic use in neonates before and after implementing home-based therapy.
Methods
Study design
In this population-based, multicentre, prospective cohort study, we included all term-born neonates who were given antibiotics during the first 72 hours of life, between 1 December 2018 and 30 November 2020. Eight neonatal departments in Eastern Denmark were included, accounting for approximately half of the Danish population of 5.8 million. Neonates prescribed antibiotics during the study period were additionally identified through the electronic medical record system (Epic). Clinical characteristics regarding mother and child were registered. Further, medical records were screened for hospital readmissions within 60 days after completing the initial antibiotic course. The population-based antibiotic use was attained from the Danish Neonatal Database.
The Board of Paediatrics (Sundhedsfagligt Råd, Pædiatri) reviewed the intravenous-to-oral switch guideline. The implementation of the guideline was granted permission by the hospital boards and the chief physicians at the neonatal Departments in Eastern Denmark.
Procedures
In Denmark, neonates with clinical signs of infection 0–72 hours after birth were recommended immediate empirical treatment with benzylpenicillin and gentamicin. Asymptomatic neonates with maternal risk factors were followed with repeated clinical examinations for 48 hours. Clinical signs of infection and maternal risk factors are defined in the online supplemental file. C reactive protein (CRP) was measured in neonates with signs of infection at the onset of antibiotic treatment and 24–48 hours after initiation.
Supplemental material
It was recommended to stop antibiotics after 48 hours in neonates with negative blood cultures if the initial signs of infection were sparse and the maximal CRP was below 50 mg/L. Probable EOI was defined as clinical signs or maternal risk factors and elevated CRP above 35–50 mg/L; proven EOI was defined by positive blood culture. Growth of coagulase-negative Staphylococcus was considered as contamination.
On 1 December 2018, the new guideline was implemented. The switch to oral antibiotics was introduced as standard treatment in term-born, clinically stable neonates with EOI (figure 1). Neonates were not offered intravenous-to-oral switch therapy if there was failure to collect blood culture or bacteraemia with Escherichia coli or bacteria resistant to amoxicillin. One millilitre was the recommended volume for blood culture.
Schematic overview of intravenous-to-oral switch treatment guideline of neonates with early-onset infection. 1Stop antibiotic treatment after 2 days if there is (1) low suspicion of clinical infection at treatment initiation, (2) no growth in blood culture and CRP of a maximum of 50 mg/L and (3) no clinical symptoms of infection at day 2. 2Clinically stable neonate defined by (1) no respiratory symptoms (no need for respiratory support), (2) no circulatory symptoms and (3) normothermia. 3The neonate should receive 3 days of coverage with gentamycin; 4Lumbar puncture should be performed if there is (1) clinical suspicion of meningitis or (2) positive blood culture. Lumbar puncture should be strongly considered when CRP is >100 mg/L. 5Written information and open admission until the last follow-up, including clinical follow-up 2 days after the switch to oral treatment, including measurement of CRP by a neonatologist, and clinical follow-up 9–12 days after treatment initiation by a paediatric nurse. CRP, C reactive protein; GA, gestational age.
Neonates were switched to oral therapy at the earliest 36–48 hours after the start of intravenous treatment and received oral amoxicillin 150 mg/kg/day in three doses. Dose scheduling was based on trough values from previously published studies.16 21–23 Neonates receiving intravenous-to-oral switch were discharged if the first dose of oral antibiotics was tolerated and there was treatment adherence. The parents received oral and written information with treatment instructions and signs of reinfection. Neonates undergoing switch therapy had a clinical follow-up and measurement of CRP 2 days after the switch to oral antibiotics and a clinical follow-up 2–4 days after treatment discontinuation. This was to reassure the neonate was well and CRP was declining. The treatment duration for probable EOI was 7 days and 7–14 days for proven EOI.
Outcome measures and definitions
The primary outcome was readmission due to probable or proven reinfection within 60 days after the initial antibiotic course was completed. The primary investigator reported the primary outcome in real time, within 24 hours, due to safety assessment. Readmissions due to suspicion of infection were managed according to a prespecified protocol. The secondary outcomes were (1) duration of hospitalisation and (2) overall use of antibiotics after the implementation compared with the pre-implementation period.
Statistical analysis
A sample size of 467 patients was estimated based on a maximum tolerable infection readmission rate of 1% (97% CI) in the oral switch group with a one-sided upper limit of the CI of 2%. Based on an approximation of intravenous-to-oral switch in 70% of eligible neonates, the study period was set to the last 2 years.
Categorical variables are presented as numbers and percentages, continuous variables as mean with SD or 95% CI and medians with corresponding IQRs, as appropriate. Neonates in the oral switch group were compared with neonates undergoing intravenous treatment only. Further, neonates with signs of infection at the initiation of antibiotic treatment were compared with neonates without signs at treatment onset. Non-parametric two-tailed Mann-Whitney U tests were used to compare continuous variables, and χ² or Fisher’s exact tests were used to compare categorical variables. P values of less than 0.05 were considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics V.28.
Results
Between 1 December 2018 and 30 November 2020, 999 of 54 622 (1.8% (95% CI 1.7% to 1.9%)) neonates received antibiotic treatment (figure 2). A total of 835 (1.5% (95% CI 1.4% to 1.6%)) received antibiotics due to suspicion of EOI, and 554 (1.0% (95% CI 0.9% to 1.1%)) received a full course of antibiotics. Antibiotic therapy was administered for 4718 days in the 999 neonates, corresponding to 86 (95% CI 83 to 89) antibiotics days per 1000 live births. Twenty-three had culture-positive EOI, that is, 0.42 (95% CI 0.27 to 0.63) per 1000 live births.
Overview of antibiotic treatment of eastern Danish neonates from 1 December 2018 to 30 November 2020.
Among the 531 neonates with culture-negative EOI, 132 (25%) had no registered signs of infection at the time of initiating antibiotics (table 1). Of these initial asymptomatic neonates, 113 (86%) had one or more maternal risk factors for EOI, and all had elevated CRP with a median maximum CRP of 76 mg/L (IQR 62–94). In neonates with signs of EOI, a smaller proportion had maternal risk factors (215 of 399 (54%), p<0.0001), and the median maximum CRP of 59 mg/L (IQR 42–82, p<0.0001) was lower when compared with neonates asymptomatic at treatment onset.
Baseline characteristics and treatment outcome in neonates with blood culture-negative infections and blood culture-positve EOI
Oral antibiotics were initiated at a median of 60 hours (IQR 48–72) after initiating intravenous treatment in the 478 neonates with culture-negative EOI who underwent intravenous-to-oral switch therapy (table 1). All neonates readily accepted the oral medication. None of the neonates had signs of infection at the time of the switch or the first follow-up visit. No patients required premature treatment discontinuation.
Readmission due to infection did not occur in neonates with culture-negative EOI who underwent switch therapy. The neonates in this group were discharged from the hospital after a median of 3.0 days (IQR 2.5–3.5) compared with 7.4 days (IQR 7.0–7.5) in the intravenous-only group. Among culture-negative cases receiving intravenous-only treatment, 1 of 53 (2%) was readmitted due to probable infection (details in online supplemental file).
Among the 23 neonates with culture-positive EOI, 11 (48%) had GBS, and 5 (22%) had Enterococcus faecalis. Three (13%) of 23 did not have signs of infection at the onset of antibiotics (table 1). Switch to oral antibiotics was done later in the neonates with culture-positive EOI compared with those with culture-negative EOI (96 hours (IQR 53–120) vs 60 hours (IQR 48–72), p<0.0001).
One (14%) of seven neonates with GBS who switched to oral antibiotics following intravenous treatment for 8 days was readmitted due to suspicion of reinfection (details in online supplemental file).
One neonate with E. coli septicaemia died on day 4 of intravenous treatment. Further, two neonates with culture-negative EOI died due to severe perinatal asphyxia and hydrops foetalis of unknown origin, respectively; both received intravenous antibiotics only.
The proportion of neonates who received a full course of antibiotics due to EOI during the first week of life was 1.2% following the implementation of intravenous-to-oral switch therapy, similar to 1.2% in the pre-implementation period (table 2).
Proportion of eastern term-born neonates in Eastern Denmark who received a full course of antibiotics due to EOI from 2017 to 2021
Discussion
In this population-based prospective multicentre study, we monitored the real-life implementation of intravenous-to-oral switch of antibiotic treatment in neonates with EOI. Intravenous-to-oral switch was assigned to 90% of all neonates with culture-negative EOI after a median of 2.5 days after initiating intravenous antibiotics. No readmissions due to infection occurred among the 478 neonates with culture-negative EOI who underwent oral therapy. In addition, the duration of hospital admission was reduced from 7 days to 3 days. Ten per cent of neonates with culture-negative EOI received a full course of intravenous antibiotics due to severe clinical manifestations.
This is the first prospective study exploring switch therapy of EOI in a real-life setting, and the results reflect routine clinical practice. Our findings complement the results of the only randomised study from high-income countries, the Efficacy and safety of switching from intravenous to oral antibiotics versus a full course of intravenous antibiotics in neonates with probable bacterial infection (RAIN) study, examining the risk of reinfection following intravenous-to-oral switch in neonates with culture-negative EOI. In the RAIN study, readmission due to reinfection occurred in 1 of 252 (0.4%) neonates undergoing intravenous-to-oral switch therapy, which was non-inferior to 1 of 252 (0.4%) receiving intravenous-only. The safety of intravenous-to-oral switch in culture-negative EOI, as found in both our prospective cohort and in the RAIN study, is supported by pharmacological studies, which have shown that oral administration of amoxicillin in clinically stable neonates results in serum concentrations surpassing the minimal inhibitory concentrations of amoxicillin of GBS for more than 50% of the time of the dosing interval.12 16 18 The safety of the intravenous-to-oral switch is also in line with results from randomised controlled trials from low-income and middle-income countries, where first-line treatment with oral antibiotics was non-inferior to intravenous treatment.13 14 However, the generalisability of these studies to high-income countries has been debated as both the settings and the risk of treatment failure were different.
The clinical management and treatment of neonates with EOI differ between countries. Stopping antibiotics if the blood culture is negative has been recommended,5 24 but no studies have systematically evaluated this approach. In our setting, neonates with symptoms, or a combination of risk factors and increased inflammatory parameters, received antibiotics for 7 days, despite a negative blood culture, resulting in antibiotic treatment of 1% of term-born neonates. Antibiotic use in Denmark appeared low compared with other countries. Only 1.8% of neonates commenced antibiotic treatment during the first 3 days of life, corresponding to 84 antibiotic days due to EOI per 1000 births. This contrasts with a multinational study, including several European countries, Australia, Canada and the USA, where a mean of 2.8% of neonates received antibiotics during the first 7 days of life, ranging from 1.2% to 12.5%.7 Despite the low use of antibiotics in Denmark, the safety of the intravenous-to-oral switch could partly reflect that a substantial proportion of the included neonates with culture-negative EOI did not have an infection.
A negative blood culture does not rule out EOI and may be due to low inoculated blood volume or transient bacteraemia.25–30 Negative blood cultures have been reported in up to 38% of neonates with bacterial meningitis.29 Therefore, managing culture-negative EOI requires a subtle balance between efficient antibiotic therapy of a condition with high morbidity and wise use of antibiotics. Nevertheless, antibiotics overuse in culture-negative EOI is very plausible as up to 20 times more neonates with negative blood cultures receive antibiotics than culture-positive cases.5 8 Thus, continued focus on antimicrobial stewardship initiatives to reduce the use of antibiotics in neonates is needed.31 Meanwhile, knowledge of the safety of antibiotic de-escalation by using a less invasive route of antibiotic administration than intravenous administration is of utmost importance as home-based oral therapy ameliorates the burden of the treatment for the neonate, the caregivers and the healthcare systems.
No randomised controlled trials have explored if oral therapy is non-inferior to intravenous antibiotics in clinically stable neonates with culture-positive EOI. A French study reported no relapse among 29 clinically stable neonates with proven GBS undergoing oral switch therapy.16 Among our cases, one neonate with confirmed GBS was readmitted due to suspicion of reinfection. This study was not powered to evaluate the safety of the intravenous-to-oral switch in EOI with proven GBS. The intravenous-to-oral switch was used contrary to guideline recommendations in four neonates with non-GBS culture-positive EOI. Using intravenous-to-oral switch in clinical practice implies a risk of undertreatment of neonates where intravenous antibiotics-only treatment is indicated. This aspect calls for continuous education and surveillance to ensure appropriate use of intravenous-to-oral switch therapy.
Limitations
The main limitation of this study was the inclusion of culture-negative cases. However, most neonates had clinical signs of infection, and those without had maternal risk factors and CRP above 50 mg/L, a higher cut-off value than those used in other countries (10–30 mg/L).5 18 32 Another limitation was that the comparison of overall antibiotic use before and after the implementation of intravenous-to-oral switch therapy was based on estimates from the Danish Neonatal Database, which is non-validated.33 Antibiotic usage was based on International Classification of Diseases, 10th Revision, diagnosis codes and seemed to be over-reported. Still, the estimates of antibiotic usage were unchanged during the years. Thus, possible systematic reporting errors were considered constant over time.
The main strengths of this study were the prospective multicentre population-based design evaluating the real-life use of intravenous-to-oral switch therapy in a large number of neonates in a setting with low antibiotic exposure. We assume our cohort was complete as the prospective cohort was validated with prescribed antibiotics during the study period and readmissions due to infection.
In conclusion, intravenous-to-oral switch therapy was readily used as 9 of 10 neonates with culture-negative EOI underwent switch therapy. In real-life clinical practice, intravenous-to-oral switch therapy was safe as no readmissions due to infection occurred among almost 500 neonates with culture-negative EOI. Knowledge of the safety of antibiotic de-escalation using oral administration is of utmost importance as the reduced need for hospitalisation ameliorates the treatment burden for neonates, their caregivers and the healthcare systems. Despite the ease of oral therapy, intravenous-to-oral switch therapy did not increase the use of antibiotics in our setting.
Data availability statement
Data are available upon reasonable request. Researchers who provide a methodologically sound proposal will be granted access to a full copy of individual deidentified data. The data will be available from 3 months after the publication of the study, ending 5 years after publication. Proposals should be directed to the corresponding author of this article, and access can be granted after the proposal is approved by the trial steering committee.
Ethics statements
Patient consent for publication
Ethics approval
Ethical approval from the National Committee on Health Research Ethics was not required since this was an implementation study. The Danish Patient Safety Authority (3-3013-1774/1) and the Danish Data Protection Agency (P-2019–05) approved the study. A waiver of the requirement of parental informed consent was obtained.
Acknowledgments
Part of this research was presented at the EAPS Conference 2022 (abstract number 593). We thank Professor Claus Klingenberg, Department of Paediatrics and Adolescence Medicine, University Hospital of North Norway, for critically reviewing the manuscript.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors ELMC, KHSD, AL, NHV, GG, BMH and UN conceptualised and designed the study, designed the data collection instruments, collected the data, carried out the initial analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript. NF-M conceptualised and designed the study and critically reviewed and revised the manuscript. LA, ST, HS, GKD, A-JLP, MB, MDS, KV and PP were involved in the data collection and critically reviewed and revised the manuscript. All authors had access to the data, approved the final manuscript as submitted and agreed to be accountable for all aspects of the work. Guarantor is ELMC.
Funding This study was funded by Innovation Fund, Denmark (0176-00020B).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.