Meningitis is associated with high mortality risk in young infants, yet the optimal treatment regimen is unclear.
To systematically evaluate the efficacy of antibiotic regimens to treat meningitis in young infants aged 0 to 59 days on critical clinical outcomes.
MEDLINE, Embase, CINAHL, WHO Global Index Medicus, and Cochrane Central Registry of Trials.
We included randomized controlled trials (RCTs) of young infants with meningitis (population) comparing the efficacy of antibiotic regimens (interventions) with alternate regimens (control) on clinical outcomes.
We extracted data on study characteristics and assessed risk of bias in duplicate. Grading of Recommendations Assessment, Development, and Evaluation was used to assess certainty of evidence.
Of 1088 studies screened, only 2 RCTs were identified. They included 168 infants from 5 countries and were conducted between 1976 and 2015. Neither study compared current World Health Organization–recommended regimens. One multisite trial from 4 countries compared intrathecal gentamicin plus systemic ampicillin/gentamicin to systemic ampicillin/gentamicin and found no difference in mortality (relative risk, 0.88; 95% confidence interval, 0.41–1.53; 1 trial, n = 98, very low certainty of evidence) or adverse events (no events in either trial arm). Another trial in India compared a 10-day versus 14-day course of antibiotics and found no difference in mortality (relative risk, 0.51; 95% confidence interval, 0.04–4.53; 1 trial, n = 70, very low certainty of evidence) or other outcomes.
Trial data on the efficacy of antibiotic regimens in young infant meningitis are scarce. Rigorous RCTs are needed to inform recommendations for optimal antibiotic regimens for meningitis treatment in this vulnerable population, particularly within the context of changing epidemiology and increasing antimicrobial resistance.
Meningitis, the infection and inflammation of the meninges and cerebrospinal fluid (CSF),1 may result in mortality and/or acute complications including ventriculitis, hydrocephalus, brain abscess, and infarction.2–4 In neonates (0–28 days), the estimated incidence of bacterial meningitis is about 0.3 to 0.4 cases per 1000 live births in high-income countries (HICs) and 0.8 to 6.1 cases per 1000 live births in low- and middle-income countries (LMICs).5,6 Neonatal meningitis is responsible for an estimated 137 deaths per 100 000 population,7 with case fatality rates ranging from an estimated 10% to 15% in HICs to 40% to 58% in LMICs.6,8,9 The highest incidence and mortality burden occur in Southeast Asia and sub-Saharan Africa (Fig 1).7 Up to 50% of surviving neonates with meningitis experience long-term sequelae, with 12% to 29% developing severe neurologic disability.4,6
The World Health Organization (WHO) makes specific recommendations for management of young infants aged 0 to 59 days given their higher mortality risk and nonspecific signs of illness. The diagnosis of meningitis in young infants is challenging because symptoms may be subtle and nonspecific in this period. Definitive diagnosis requires CSF culture, which is often not feasible in low-resource settings or among critically unstable infants. The WHO Hospital Pocketbook defines clinical meningitis symptoms in young infants as irritability, lethargy, unconsciousness, convulsions, vomiting, abnormal movements (or behavior), seizures, a high-pitched cry, and/or a bulging fontanelle.10 In community settings, Integrated Management of Childhood Illness guidelines are used to identify potential meningitis in young infants with signs of possible severe bacterial infection (convulsions, unable to feed, and no movement, in addition to high or low body temperature, fast breathing, or severe chest-indrawing).11
The etiology, or causative organisms, of meningitis vary by region and setting. Group B Streptococcal (GBS) species and gram negative bacilli have been frequently reported as causative organisms of neonatal meningitis in both high-income and lower-middle income settings, (Supplemental Figure 5) with gram-negative meningitis species demonstrating an increasing incidence in both settings.7,9 This rise in gram-negative infections has been accompanied by an increase in multidrug resistance in HICs12 and LMICs, limiting treatment options.13,14
Current WHO AWARE (Access, Watch, Reserve) and WHO Hospital Pocketbook recommendations for treatment of young infant meningitis include intravenous (IV) ampicillin (or third-generation cephalosporin: cefotaxime or ceftriaxone) and gentamicin as a first-choice antibiotic for clinically diagnosed or suspected meningitis. Second-choice antibiotic is IV meropenem when resistant gram-negative organisms are suspected. Treatment is recommended to continue for up to 3 weeks for an unknown pathogen and should occur in a hospital.10,15 These guidelines were formed on the basis of early trials and expert opinion, and remain largely consistent with recommendations made as early as 50 years ago.16 However, changing epidemiology and antimicrobial resistance (AMR) profiles warrant revisiting the evidence and potentially updating recommendations.12 Our objective was to systematically review the published literature to determine the efficacy of antibiotic regimens for suspected meningitis in young infants on critical outcomes: mortality, clinical improvement or deterioration, neurodevelopmental outcomes, and adverse effects.
Methods
Search Strategy and Screening
We systematically searched MEDLINE, Embase, Cinahl, WHO Global Index Medicus, and Cochrane Central Registry of Trials up to April 15, 2023. Our search strategy included terms for “infant”, “meningitis”, “antibiotics” and “randomized controlled trials”. The full search strategy is available in Supplemental Appendix 1. We also hand-searched key reviews and systematic reviews related to young infant meningitis to identify additional studies that might meet our inclusion criteria. We first screened studies by title/abstract and then by full text. All studies were screened independently by 2 different reviewers with conflicts adjudicated by an independent third reviewer at all stages of screening. Screening was conducted using Covidence systematic review software.17
Inclusion/Exclusion Criteria
We included individual and cluster randomized controlled trials (RCTs) that included any type, combination, or route of antibiotics for meningitis. We excluded observational or quasi-experimental studies, interventions that were prophylactic or risk-based, treatment with antiviral, antifungal, or antiparasitic medications, unpublished gray literature, pharmacokinetic studies, and those without full text. We had no limitations based on language or publication date.
Population
We included studies reporting upon infants <60 days postnatal age who presented with clinical or laboratory confirmed meningitis (as defined by the trialist). Studies enrolling infants >60 days were included only if there was a subgroup analysis presenting outcomes among infants <60 days of age. No limitations were placed on site of presentation or clinical care settings (hospital, clinic, or community).
Intervention
We included studies evaluating any antibiotic regimen intended to treat meningitis in young infants as the intervention group. The “intervention” considered was antibiotic type, dose, duration, or mode of delivery. We included studies evaluating antibiotic regimens in isolation or as a component of a package of interventions.
Comparator
We included studies with any comparator group including standard of care, an alternate antibiotic regimen, or an alternate management strategy such as referral or observation.
Outcome Measures
Critical outcomes of interest were mortality (all-cause or infection-specific), clinical improvement or deterioration, neurodevelopmental outcomes, and adverse effects. Secondary outcomes included hospital utilization, such as length of stay or readmission, relapse, and cost effectiveness.
Data Extraction and Analysis
All data were independently extracted in duplicate into a predesigned excel sheet with discrepancies adjudicated by a third author. For dichotomous outcomes, we entered event rates (numerators, denominators, and percentages). For continuous outcomes, we collected mean/standard deviation or median/interquartile range. We also extracted unadjusted and adjusted effect sizes, and intention-to-treat and per-protocol outcomes as available. Risk ratios (RRs) and confidence intervals (CIs) were calculated and figures were generated using R statistical software (version 4.3.2)18; Choropleth maps (shaded geographical maps to represent normalized data) were generated using Datawrapper.19
Risk of Bias Assessment
We used the revised Cochrane risk-of-bias tool for randomized trials to assess the risk of bias among included studies. Risk of bias was independently assessed in duplicate with consensus discussion among investigators for final assignment in case of discrepancies. A study was deemed to have an overall high risk of bias if there was high risk in any 1 domain or some risk in 3 or more domains. A study was deemed to have overall some concerns of risk of bias if there were some concerns of risk in 1 or 2 domains. A study was deemed to have overall low risk of bias if there was low risk in every domain.
GRADE Assessment
Certainty of evidence (COE) for the effects of interventions on individual outcomes was assigned using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methods and Gradepro software.20 For each outcome, we assessed and categorized the certainty of the evidence as very low, low, moderate, or high certainty, based on risk of bias, inconsistency, indirectness, imprecision, and presence of publication bias using standard GRADE criteria. Details regarding the GRADE methods for this review are included in Supplemental Appendix 2.21
Results
Search Results
A total of 1088 titles and abstracts were screened for eligibility. Sixty were selected for full-text review and 2 RCTs were included in the systematic review (Fig 2). The 2 RCTs included 168 infants from 5 countries (Canada, Colombia, Mexico, USA, India). Among the 58 excluded studies, the most common reason for exclusion was participant age (Supplemental Table 3 contains a list of all excluded studies). Both included trials were hospital-based studies on infants ≤30 days and excluded infants with congenital central nervous system anomalies. Neither trial compared the WHO-recommended antibiotic regimen with an alternative.
Current WHO Regimens
We did not identify any trials that studied current WHO first- or second-choice antibiotic regimens. Details on study characteristics are presented in Table 1 and Supplemental Table 4, and reported outcomes are presented in Table 2.
Characteristics of Included Studies
| Author and Year | Study Setting | Population | Sample Size | Intervention | Comparator | Primary Outcome |
|---|---|---|---|---|---|---|
| McCracken 1976 | USA, Canada, Mexico, and Colombia Hospital-based | Infants with enteric gram-negative meningitis | 98 | IT gentamicin × 3 d AND comparator regimen | IV ampicillin + IM gentamicin) × 3 wk or 2 wk after CSF sterilization | Mortality |
| Mathur 2015 | India Hospital-based | Neonates with meningitis who have achieved clinical remission by day 7 of antibiotics | 70 | 10- day course of antibiotics | 14-day course of antibiotics | Treatment failure, clinical sepsis, and mortality within 28 d of enrollment |
| Author and Year | Study Setting | Population | Sample Size | Intervention | Comparator | Primary Outcome |
|---|---|---|---|---|---|---|
| McCracken 1976 | USA, Canada, Mexico, and Colombia Hospital-based | Infants with enteric gram-negative meningitis | 98 | IT gentamicin × 3 d AND comparator regimen | IV ampicillin + IM gentamicin) × 3 wk or 2 wk after CSF sterilization | Mortality |
| Mathur 2015 | India Hospital-based | Neonates with meningitis who have achieved clinical remission by day 7 of antibiotics | 70 | 10- day course of antibiotics | 14-day course of antibiotics | Treatment failure, clinical sepsis, and mortality within 28 d of enrollment |
CSF, cerebrospinal fluid; IM, intramuscular; IT, intrathecal.
Summary of Findings
| Summary of Findings | |||||
|---|---|---|---|---|---|
| McCracken 1976: Intrathecal and Systemic Antibiotic Therapy Compared With Systemic Antibiotic Therapy | |||||
| Outcome | No. of Participants | Event Rate With Systemic Antibiotic Therapy | Event Rate With Intrathecal and Systemic Antibiotic Therapy | Relative Risk (95% CI) | GRADE Certainty |
| Mortality | 98 | 17/56 (30.4%) | 11/42 (26.2%) | RR 0.88 (0.41–1.53) | Very Low |
| Adverse effects of antibiotic therapy | 98 | 0/56 (0.0%) | 0/42 (0.0%) | Not estimable | Very Low |
| Mathur 2015: 10 d Course of Systemic Antibiotic Therapy Compared With 14 d Course of Systemic Antibiotic Therapy | |||||
| Outcome | No. of participants | Event rate with 14-d course of antibiotic therapy | Event rate with 10-d course of antibiotic therapy | Relative Risk (95% CI) | GRADE certainty |
| Treatment failure | 70 | 0/35 (0.0%) | 0/35 (0.0%) | Not estimable | Very Low |
| Clinical sepsis | 70 | 3/35 (8.6%) | 0/35 (0.0%) | Not estimable | Very Low |
| Mortality | 70 | 2/35 (5.7%) | 1/35 (2.9%) | RR 0.51 (0.04–4.53) | Very Low |
| Sensorineural hearing loss | 70 | 0/35 (0.0%) | 1/35 (2.9%) | Not estimable | Very Low |
| Neurologic sequelae | 70 | 0/35 (0.0%) | 0/35 (0.0%) | Not estimable | Very Low |
| Adverse effects of antibiotic therapy | 70 | 0/35 (0.0%) | 0/35 (0.0%) | Not estimable | Very Low |
| Summary of Findings | |||||
|---|---|---|---|---|---|
| McCracken 1976: Intrathecal and Systemic Antibiotic Therapy Compared With Systemic Antibiotic Therapy | |||||
| Outcome | No. of Participants | Event Rate With Systemic Antibiotic Therapy | Event Rate With Intrathecal and Systemic Antibiotic Therapy | Relative Risk (95% CI) | GRADE Certainty |
| Mortality | 98 | 17/56 (30.4%) | 11/42 (26.2%) | RR 0.88 (0.41–1.53) | Very Low |
| Adverse effects of antibiotic therapy | 98 | 0/56 (0.0%) | 0/42 (0.0%) | Not estimable | Very Low |
| Mathur 2015: 10 d Course of Systemic Antibiotic Therapy Compared With 14 d Course of Systemic Antibiotic Therapy | |||||
| Outcome | No. of participants | Event rate with 14-d course of antibiotic therapy | Event rate with 10-d course of antibiotic therapy | Relative Risk (95% CI) | GRADE certainty |
| Treatment failure | 70 | 0/35 (0.0%) | 0/35 (0.0%) | Not estimable | Very Low |
| Clinical sepsis | 70 | 3/35 (8.6%) | 0/35 (0.0%) | Not estimable | Very Low |
| Mortality | 70 | 2/35 (5.7%) | 1/35 (2.9%) | RR 0.51 (0.04–4.53) | Very Low |
| Sensorineural hearing loss | 70 | 0/35 (0.0%) | 1/35 (2.9%) | Not estimable | Very Low |
| Neurologic sequelae | 70 | 0/35 (0.0%) | 0/35 (0.0%) | Not estimable | Very Low |
| Adverse effects of antibiotic therapy | 70 | 0/35 (0.0%) | 0/35 (0.0%) | Not estimable | Very Low |
CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development, and Evaluation.
Route of Antibiotic Administration
One trial (McCracken 1976) was an individually randomized, hospital-based, multisite study based in Canada, Colombia, Mexico, and USA, and enrolled 98 infants aged ≤30 days, with gram-negative enteric bacterial meningitis.22 This trial compared intrathecal gentamicin for 3 days plus IV ampicillin plus intramuscular gentamicin for 3 weeks (intervention) to the ‘standard’ regimen of ampicillin IV plus gentamicin intramuscular for 3 weeks (comparator), and followed infants until 48 months postnatal age. This trial found no significant differences in mortality among those who received gentamicin intrathecal for 3 days in addition to systemic ampicillin/gentamicin for 3 weeks, compared with systemic ampicillin/gentamicin for 3 weeks (RR, 0.88; 95% CI, 0.41–1.53; 1 trial, n = 98). It also reported no adverse events of medication among both groups. Neurodevelopmental outcomes were assessed but not reported for the age group <60 days. It did not report on differences in treatment success or failure (Table 2 and Supplemental Table 5). The McCracken trial (1976) had an overall high risk of bias because of some concerns for bias in the process of randomization and high risk of bias with respect to deviation from intended assignment to intervention (Fig 3, Supplemental Fig 4, and Supplemental Table 6). Evidence was of very low certainty for both outcomes because of a high risk of bias, the presence of a single study with a small sample size and imprecise estimates (Supplemental Table 5).
Duration of Antibiotics
The second RCT (Mathur 2015) was an individually randomized, hospital-based RCT conducted in India that enrolled 70 neonates with meningitis.23 This trial compared a 10-day course of antibiotics (intervention) with a 14-day course of antibiotics (comparator) in 70 neonates; the type of antibiotic and route of administration was not indicated in the manuscript. This trial reported on treatment failure, mortality, adverse effects of medication, and adverse neurodevelopmental outcomes within a 28-day period from enrollment. It found no significant differences in mortality between those treated with the 10-day course of antibiotics compared with the 14-day course of antibiotics (RR, 0.51; 95% CI, 0.04–4.53; 1 trial, n = 70). No cases of clinical sepsis were reported in the control group and no cases of treatment failure, neurologic sequelae and adverse effects were reported in either arm of the study. Only 1 case of sensorineural hearing loss was noted in the study arm. (Table 2 and Supplemental Table 5) The Mathur trial (2015) had an overall low risk of bias and scored low in all domains (Fig 3, Supplemental Fig 4, and Supplemental Table 6). The COE was very low for all outcomes because of the presence of a single study with a small sample size, imprecise estimates, and the lack of events reported in either arm for most outcomes (Supplemental Table 5).
Discussion
Our systematic review revealed only 2 trials that examined the efficacy of antibiotic treatment of meningitis in young infants aged 0 to 59 days, 1 of which was more than 40 years old. Neither investigated antibiotic regimens in current practice, and the overall COE was very low for every critical outcome.
Currently, WHO AWARE and WHO Hospital Pocketbook recommends systemic ampicillin (or third-generation cephalosporins as an alternative) and gentamicin as a first-choice treatment option for young infant meningitis, up to a period of 21 days for an unknown pathogen. We did not identify any previous systematic reviews of WHO regimens for young infant meningitis, and we found no RCTs examining the efficacy of this regimen.
Reduction in the duration of antibiotics may reduce the risk of AMR, in addition to reducing length of hospitalization and exposure to potentially painful procedures. A 2022 systematic review on duration of antibiotic therapy for neonatal meningitis24 identified only 1 observational study25 that evaluated different durations of antibiotic therapy, in addition to the RCT included in this review.23 Zhao 2019xx found that the prevalence of poor outcomes (death/moderate-severe neurologic disability) was higher among those with shorter antibiotic regimens (58.3% with poor outcomes among the 4- to 10-day arm vs 17.6% without for >10 days [n = 200, P < .0001]; 35% with poor outcomes in the 4- to 14-day arm vs 16.9% without for >14 days [n = 202, P = .009]; and 28.8% with poor outcomes in the 4- to 18-day arm vs 15.6% without for >18 days [n = 200, P = .028]). The study reported no difference in clinical outcomes with durations longer than 21 days (24.1% with poor outcomes in the 4- to 21-day arm vs 19.0% without for >21 days; n = 200, P = .471). However, these results were not adjusted for risk factors and illness severity, and the study was not adequately powered to demonstrate equivalence.25 Another 2023 nonrandomized intervention study of 80 neonates from India, published after the systematic review previously referenced, compared a 21-day antibiotic course (WHO-recommended regimen) with a 14-day course for neonatal meningitis. The study found no difference in recurrence of sepsis or meningitis, mortality, or adverse neurologic sequelae in both arms 28 days after initiation of antibiotics.26 Both studies were limited by a lack of randomization, small sample sizes, and observational study design.
Regimen recommendations of using a β-lactam and aminoglycoside combination to empirically treat neonatal meningitis have remained consistent over the past 50 years or so.16 A Cochrane systematic review from 2004 reported inadequate evidence to recommend an optimal empirical antibiotic regimen.27,28 A β-lactam and aminoglycoside combination provides coverage against the most common causative organisms for neonatal meningitis (GBS, Escherichia coli).29,30 However, poor CSF penetration of gentamicin and toxicity concerns have prompted several observational studies on alternative empirical antibiotic regimens.
Cefotaxime has often been recommended in combination with ampicillin (for Listeria and enterococcal coverage) for suspected meningitis, particularly in high risk populations such as VLBW (very low birth weight) infants.12,31,32 Studies have shown that the use of cefotaxime has been associated with increased risk of extended-spectrum β-lactamase producing Enterobacteriaceae infections and invasive fungal infections.28,33 One retrospective cohort study comparing empirical antibiotic regimens among 128 914 neonates found higher adjusted odds of mortality among those treated with cefotaxime/ampicillin compared with ampicillin/gentamicin.34
The National Institutes of Health and Care Excellence recently updated their neonatal meningitis guidelines in March 2024 based on a systematic review of RCT and observational data,35 surveillance of updated evidence,36 and committee expert opinion.37 For uncomplicated neonatal meningitis from an unknown pathogen, cefotaxime and amoxicillin IV are recommended. The American Association of Pediatrics clinical practice guidelines recommend IV ampicillin with ceftazidime for treatment of meningitis in well-appearing infants age 8 to 28 days, and ceftriaxone and vancomycin for infants between 29 and 60 days of age.36 All these recommendations were based on expert opinion.39,10
Antimicrobial resistance patterns are changing with increasing reports of multidrug-resistant infections in NICUs in both HICs and LMICs.13,14,41,42 Carbapenem-resistant Enterobacter and extended-spectrum β-lactamase producing Enterobacteriaceae infections are particularly common.43 In this context of changing AMR patterns, there have been calls to revise current antibiotic recommendations for appropriate coverage while limiting medication side effects.12,29 There have been efforts to study alternatives among neonates: 1 review did identify 5 potential antibiotics (amikacin, tobramycin, fosfomycin, cefepime, and flomoxef) but noted that further research into efficacy and pharmacodynamics is required.44
Among antibiotics recommended by WHO, ampicillin and third- and fourth-generation cephalosporins have good CSF penetration with IV delivery, making them ideal for meningitis treatment. Pathogen clearance of CSF correlates with clinical improvement.30 IV aminopenicillins and third- and fourth-generation cephalosporins have demonstrated high CSF:plasma concentration ratios, particularly in the presence of meningeal inflammation.45 One observational study from the 1960s in neonates (aged 28 days and younger) with culture-proven bacterial meningitis found high CSF levels of parenteral penicillin and ampicillin (10-100 times higher than gram positive bacterial minimum inhibitory concentrations [MICs]) and rapid bacterial clearance from CSF within 72 hours.30 Among cephalosporins, cefotaxime has traditionally been preferred over ceftriaxone because of its lower affinity for plasma proteins, and the potential lower risk of hyperbilirubinemia from bilirubin displacement.29,46 Two recent studies have not shown increased risk of hyperbilirubinemia among term infants treated with ceftriaxone.47,48 In a recent systematic review, investigators concluded that the data were inadequate to determine the association of ceftriaxone administration and hyperbilirubinemia given the small sample sizes, poor external validity, and inconsistent outcomes ascertainment.49
Aminoglycosides, however, have poor CNS penetration with parenteral (IV or IM) administration.45 McCraken (1972) showed that with parenteral administration, CSF aminoglycoside levels approximated MIC of common gram-negative enteric organisms, but higher levels were difficult to achieve with parenteral administration. Gram-negative CSF samples from this cohort demonstrated delayed clearance, after about 2 to 3 weeks of therapy, which is supportive of current meningitis treatment duration recommendations.30
A few older studies from the 1970s and 1980s have examined alternate routes of antibiotic administration to achieve higher CSF concentrations. Although higher CSF aminoglycoside levels exceeding bacterial MICs have been demonstrated with intraventricular administration50,51 and intrathecal administration,45 safety is an important concern. A single trial in 1980, identified as the only RCT by 2 systematic reviews,52,53 found significantly higher mortality rates among those receiving intraventricular aminoglycoside for meningitis in infants. The trial was discontinued and discouraged further trials in this area.54 This study was excluded from our systematic review due to the age of participants. The 1 trial of intrathecal antibiotic administration included in our review (McCracken 1976)22 showed no differences in clinical outcomes between the 2 study arms. The sample size was small and findings should be interpreted with caution given safety considerations.
In this systematic review, we searched a range of databases from inception and used rigorous methods. However, we only identified 2 trials that met our inclusion criteria. Our main limitation was the exclusion of observational studies.
There are fewer trials in neonatal populations compared with adults,55 possibly because of the inherent complexities of these trials, including neonatal predisposition to drug toxicity, increased expense and liability, and decreased return on investment for trial sponsors.55,56 Altered pharmacokinetics of antibiotics in neonates, particularly high-risk populations (preterm, very low birth weight), make identifying and studying alternative regimens more challenging in this population.29,45,57 Furthermore, changing epidemiology, incidence rates of meningitis, and local AMR profiles have narrowed treatment options, posing a challenge in clinical practice. In the absence of robust data, it is challenging for guidelines to evolve in accordance with the changing epidemiologic and AMR landscape. Rigorous, high-quality trials are thus needed to study different antibiotic regimens and identify newer regimens with appropriate coverage, safer side effect profiles, better CSF penetration, and optimal durations.
Conclusions
Current guidelines for the management of meningitis in young infants are similar to recommendations from 50 years ago, despite evolving epidemiology and AMR patterns.16 Rigorous, adequately powered clinical trials in this area are urgently needed to update WHO recommendations for antibiotic regimens and duration of therapy for young infant meningitis, accounting for changing epidemiology and AMR patterns, as well as CSF penetration and side effect profiles.
Dr Mathias screened studies, extracted data, analyzed and interpreted the data, drafted the initial manuscript, reviewed and revised the manuscript, and approved the final manuscript as submitted; Dr North designed the study, screened studies and interpreted data, reviewed and revised the manuscript, and approved the final manuscript as submitted; Dr Santana screened studies, extracted and interpreted data, reviewed the manuscript, and approved the final manuscript as submitted; Dr Britto screened studies, analyzed and interpreted data, reviewed and revised the manuscript, and approved the final manuscript as submitted; Dr Fung conceptualized and designed the study, reviewed and revised the manuscript, and approved the final manuscript as submitted; Dr Chou provided inputs on the methodology and presentation of the results, reviewed and revised the manuscript, and approved the final manuscript as submitted; Ms Wade developed and ran the search strategy through multiple databases to compile our list of studies for screening, reviewed the manuscript, and approved the final manuscript as submitted; Dr Edmond conceptualized the study, provided inputs on the presentation of the results, reviewed and revised the manuscript, and approved the final manuscript as submitted; Dr Lee obtained funding, designed the study, interpreted data, reviewed and revised the manuscript, and approved the final manuscript as submitted; and all authors approved the final manuscript as submitted and all authors agree to be accountable for all aspects of the work.
PROTOCOL REGISTRATION: Prospero registration: CRD42023431387. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023431387; data are available on request.
FUNDING: Brigham and Women’s Hospital received funding from the World Health Organization (WHO) to complete this work. The sponsor (WHO) commissioned the review for the guideline development group meeting for development of WHO recommendations on management of serious bacterial infection in young infants aged 0 to 59 days. The sponsor provided inputs on the presentation of the results and manuscript.
CONFLICT OF INTEREST DISCLOSURES: Dr Edmond is an employee of the sponsor, the World Health Organization (WHO). Dr Chou is the Grading of Recommendations Assessment, Development, and Evaluation methodologist for the WHO guidelines for management of severe bacterial infections in infants aged 0 to 59 days. other authors have indicated they have no potential conflicts of interest to disclose.
- AMR
antimicrobial resistance
- AWARE
Access, Watch and Reserve (antimicrobials)
- CI
confidence interval
- COE
certainty of evidence
- CSF
cerebrospinal fluid
- GRADE
Grading of Recommendations Assessment, Development, and Evaluation
- HIC
high-income country
- IV
intravenous
- LMIC
lower- and middle-income country
- MIC
minimum inhibitory concentration
- NICE
National Institute for Health and Care Excellence (United Kingdom)
- RCT
randomized controlled trial
- RR
relative risk
- WHO
World Health Organization
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