Evidence reviews for antibiotics for bacterial meningitis before or in the absence of identifying causative infecting organism in younger infants

Cover of Evidence reviews for antibiotics for bacterial meningitis before or in the absence of identifying causative infecting organism in younger infants

Evidence reviews for antibiotics for bacterial meningitis before or in the absence of identifying causative infecting organism in younger infants

Meningitis (bacterial) and meningococcal disease: recognition, diagnosis and management

Evidence review D1

NICE Guideline, No. 240

London: National Institute for Health and Care Excellence (NICE); 2024 Mar.

ISBN-13: 978-1-4731-5762-0

Antibiotics for bacterial meningitis before or in the absence of identifying causative infecting organism in younger infants

Review question

What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants (excluding neonates) before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

Introduction

Bacterial meningitis is a rare but serious infection. In younger infants, the range of bacterial aetiologies differs from those seen in older infants, children and most adults.

The aim of this review is to establish the appropriate empirical antibiotic treatment regimen(s) that are effective in treating suspected bacterial meningitis in younger infants, before, or in the absence of identifying, the causative infecting organism.

Summary of the protocol

See Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.

Table 1

Summary of the protocol (PICO table).

For further details see the review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document (supplementary document 1).

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

Effectiveness evidence

Included studies

A systematic review of the literature was conducted but no studies were identified which were applicable to this review question.

See the literature search strategy in appendix B and study selection flow chart in appendix C.

Excluded studies

Studies not included in this review are listed, and reasons for their exclusion are provided in appendix J.

Summary of included studies

No studies were identified which were applicable to this review question (and so there are no evidence tables in Appendix D). No meta-analysis was conducted for this review (and so there are no forest plots in Appendix E).

Summary of the evidence

No studies were identified which were applicable to this review question (and so there are no GRADE tables in Appendix F).

Economic evidence

Included studies

A single economic search was undertaken for all topics included in the scope of this guideline, but no economic studies were identified which were applicable to this review question.

Economic model

No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation. This was because the choice of antibiotics in this population is quite limited, and the costs are generally similar and relatively inexpensive. Furthermore, local patterns of antibiotic resistance and allergies can also constrain the decision set.

The committee’s discussion and interpretation of the evidence

The outcomes that matter most

Bacterial meningitis is associated with high rates of mortality and morbidity, and antibiotics are the mainstay of treatment for bacterial meningitis. Therefore, all-cause mortality and long-term neurological impairment were prioritised as critical outcomes because of the severity of these outcomes. Severe developmental delay was prioritised as a critical outcome while functional impairment was chosen as an important outcome because severe developmental delay is a more relevant and important outcome in babies and children.

In addition to functional impairment, epilepsy or seizures, hearing impairment and serious intervention-related adverse effects were chosen as important outcomes because these outcomes are relatively common after bacterial meningitis and may be related to antibiotic therapy.

The quality of the evidence

No studies were identified which were applicable to this review question.

Benefits and harms

No evidence was identified for the effectiveness of antibiotic treatment regimens in young babies (aged 29 days to 3 months) with suspected bacterial meningitis. Therefore, the committee made recommendations based on their clinical knowledge and experience.

The committee discussed common infective organisms (for example, Escherichia coli, Streptococcus pneumoniae and Neisseria meningitidis) in this age group and agreed to recommend intravenous ceftriaxone for suspected bacterial meningitis in young babies in line with the British National Formulary for Children (BNFC) (Paediatric Formulary Committee 2022). The committee were aware that insufficient dose can increase the risk of treatment failure and antibiotic resistance; therefore, they agreed to use the maximum dose recommended by the BNFC or follow local antimicrobial guidance. The committee highlighted the practical and resource-use advantages associated with ceftriaxone because it has a broad spectrum of activity, and the long half-life means that it can be given only once a day. The committee acknowledged some concerns with once daily administration in that a second dose might need to be delayed if the first dose of ceftriaxone was administered outside of routine working hours; however, they were aware that a second dose can be given earlier, to shift the administration time, if there is a minimum of 12 hours between doses (Gbesemete 2019).

The committee discussed some reasons why in clinical practice (particularly in intensive care units) cefotaxime might be given instead of ceftriaxone. For instance, to minimise the time that intravenous lines are being used for administering antibiotics, which might be needed for other medications, due to ceftriaxone typically being infused over 30 minutes intravenous and cefotaxime being given as a bolus. However, the committee agreed that this practice is not necessary, as ceftriaxone can be given as bolus. Sometimes there may be a reaction (for example, vomit reflex) if ceftriaxone is administered too quickly, but in the committee’s experience this is relatively rare, which was supported by a recent study (Patel 2021). The committee agreed that ceftriaxone should be given as first-line treatment for suspected bacterial meningitis when the causative organism has not been identified, unless contraindicated (as outlined in the BNFC) in which case cefotaxime can be considered.

The committee highlighted the importance of considering the possibility of a cephalosporin-resistant pneumococcus causing bacterial meningitis. The committee were aware that the previous NICE guideline on meningitis (NICE 2010) recommended to treat people who have travelled outside the UK or had prolonged or multiple exposure to antibiotics within the last 3 months with vancomycin (in addition to the cephalosporin). However, they discussed that practice has changed since the previous NICE guideline and agreed that changes to this recommendation were required. Firstly, the committee were aware that current practice is to use rifampicin or linezolid in addition to a cephalosporin where the cephalosporin itself might be insufficient due to resistance. However, the committee highlighted that there is not enough evidence about the effectiveness and safety of rifampicin or linezolid in suspected (or confirmed) cephalosporin resistant bacterial meningitis to support recommending them. Therefore, the committee recommended that, clinicians should seek advice from an infection specialist (a microbiologist or infectious diseases specialist) for all cases of bacterial meningitis, but this was particularly important if cephalosporin resistance is suspected in young babies who have recently travelled abroad. Secondly, the committee noted that the evidence used to inform the recommendation about prolonged or multiple exposure to antibiotics in the previous guideline came from Canada (Vanderkooi 2005), which has a higher prevalence of cephalosporin resistance than the UK. The committee discussed that there was insufficient evidence that prolonged or multiple exposure to antibiotics on an individual level causes people to be colonised with resistant organisms. Rather, the committee agreed that it is antibiotic use at a population level that contributes to cephalosporin resistant bacteria. Therefore, the committee agreed that the evidence did not warrant recommending different treatment for these people. Moreover, the committee noted that, in their experience, such people are not currently treated differently. The committee were aware that Enterobacterales (coliforms) are relatively common in young babies and tend to be resistant to cephalosporins. Therefore, the committee agreed that alternative antibiotics may be needed for young babies colonised with cephalosporin-resistant Enterobacterales (coliforms) who develop bacterial meningitis. In the absence of evidence on the effectiveness of antibiotic regimens in this group, the committee recommended that infection specialist advice is sought where cephalosporin resistance is suspected.

There was no evidence found on antibiotic use for suspected bacterial meningitis in young babies with an antibiotic allergy, but the committee agreed it was important to make a recommendation for this population. Based on their knowledge and experience, the committee agreed that cephalosporin-induced anaphylaxis is rare, and the risk-benefit balance of cephalosporin relative to chloramphenicol is favourable in the majority of people with non-severe allergy. Therefore, the committee agreed that clinicians should seek information about the nature of the allergy and advice from an infection specialist before making a treatment decision. The committee acknowledged that it is important that treatment is not delayed; however, they agreed that information about the nature of allergy is often readily available from the patient’s parents or guardians. The committee agreed that ceftriaxone should still be considered if the nature of the allergic reaction they get is not severe, in accordance with the first line treatment recommended above. However, if the allergic reaction is severe, alternatives to ceftriaxone will be needed. The committee discussed that chloramphenicol is commonly used in the case of severe beta-lactam allergy, but they were aware that its spectrum of activity does not cover Enterobacterales (coliforms). However, the committee acknowledged that meningitis caused by Enterobacterales (coliforms) is rare and typically happens only in the first weeks of life where you would not see an anaphylactic reaction, so in practice this situation would rarely occur. For young babies with severe allergic reactions, the committee recommended chloramphenicol.

The committee noted that listeria is not susceptible to ceftriaxone or cefotaxime based on their clinical knowledge and experience, and whilst listeria is most common in older adults, risk factors for listeria should also be considered in young babies. The committee were aware that amoxicillin is recommended by the BNFC (Paediatric Formulary Committee 2022) for meningitis caused by listeria monocytogenes (in combination with another antibiotic). Therefore, the committee recommended that intravenous amoxicillin should be part of the first line treatment described above for young babies with risk factors for listeria.

The committee agreed it was important to make a recommendation about appropriate antibiotic treatment for young babies with risk factors for Listeria monocytogenes and a history of antibiotic allergy. The committee were aware that current practice would be to consider the use of co-trimoxazole for both severe and non-severe allergic reactions, rather than amoxicillin, in addition to the first line treatment recommended above for people with a history of antibiotic allergy and, in line with current practice, recommended co-trimoxazole (in addition to cephalosporin for non-severe allergy or in addition to chloramphenicol for severe allergy) for young babies with an antibiotic allergy who have risk factors for Listeria monocytogenes.

The committee were aware that the previous NICE guideline on bacterial meningitis made recommendations about the use of antibiotics for herpes simplex encephalitis. The committee acknowledged that this condition was not included in the scope for the current guideline. The committee were aware that prescribing aciclovir has become routine practice in cases of suspected bacterial meningitis (Hagen 2020) and were concerned about the overuse of aciclovir. Therefore, the committee made a recommendation to clarify that aciclovir should only be given when herpes simplex encephalitis is strongly suspected.

The committee agreed that there should be a recommendation about duration of antibiotic treatment. The committee were aware that the results of confirmatory tests could be available within 48 to 72 hours and recommended that empirical antibiotic treatment should be continued until results suggest an alternative treatment is needed, or there is an alternative diagnosis, which is in line with current practice. The committee agreed that it was necessary to specify a duration of antibiotic treatment for cases where the CSF parameters are consistent with bacterial meningitis, but the blood culture and whole-blood diagnostic PCR are negative. The committee acknowledged that different durations of antibiotic therapy are needed for different causative organisms. Given that Streptococcus pneumoniae and Neisseria meningitidis are common causes of bacterial meningitis in this age group, the committee agreed that the duration of antibiotic treatment should be consistent with the treatment recommended for these causative organisms and as 10 days is the longer duration of treatment prior to review (recommended for Streptococcus pneumoniae meningitis) this was considered the most appropriate default duration to recommend in culture negative cases. The committee also agreed that advice from an infection specialist should be sought if young babies have not recovered after 10 days.

Cost effectiveness and resource use

This review question was not prioritised for economic analysis and therefore the committee made a qualitative assessment of the likely cost-effectiveness of their recommendations. No evidence was identified for the effectiveness of antibiotic treatment regimens in young babies. The committee reasoned that it would be cost-effective to recommend ceftriaxone for young babies, as it is potentially less resource intensive as it can be given once a day compared to cefotaxime which is given 3 times daily. As these recommendations were in line with current NHS practice and updates made to the BNFC since the previous guideline, no significant resource impact is anticipated.

The committee also made recommendations outlining when infection specialist advice should be sought reflecting their view that the cost-effective choice of antibiotic would depend on the specific individualised characteristics of the presenting young baby, such as in cases of suspected or confirmed cephalosporin resistant bacterial meningitis.

Recommendations supported by this evidence review

This evidence review supports recommendations 1.6.4 to 1.6.9 and 1.6.16. Other evidence supporting these recommendations can be found in evidence reviews on antibiotic regimens for bacterial meningitis before or in the absence of identifying causative infecting organism in older infants and children, and adults (see evidence reviews D2 and D3) and for specific causative organisms (see evidence reviews E1 to E6).

References – included studies

Effectiveness

No studies were identified which were applicable to this review question.

Economic

No studies were identified which were applicable to this review question.

Other

Gbesemete 2019
Gbesemete, D., Faust, S. (2019). Prescribing in infection: antibacterials. In. Barker, C., Turner, M., Sharland, M. (Eds.) Prescribing Medicines for Children: From drug development to practical administration, Pharmaceutical Press, London: UK
Hagen 2020
Hagen, A., Eichinger, A., Meyer-Buehn, M. et al. (2020). Comparison of antibiotic and acyclovir usage before and after the implementation of an on-site FilmArray meningitis/encephalitis panel in an academic tertiary pediatric hospital: a retrospective observational study, BMC Pediatrics 20(1), 56 [PMC free article: PMC7001287] [PubMed: 32020860]
NICE 2010
National Institute for Health and Care Excellence (2010). Meningitis (bacterial) and meningococcal septicaemia in under 16s: recognition, diagnosis and management. Available at: https://www.nice.org.uk/guidance/cg102 [Accessed 04/04/2022] [PubMed: 32207890]
Paediatric Formulary Committee 2022
Paediatric Formulary Committee. BNF for Children (online). London: BMJ Group, Pharmaceutical Press, and RCPCH Publications. Available at: http://www.medicinescomplete.com [Accessed 29/03/2022]
Patel 2021
Patel, S., Green. H., Gray, J., Rutter, M., Bevan, A., Hand, K., Jones, C. E., Faust, S. N. (2021). Evaluating Ceftriaxone 80 mg/kg Administration by Rapid Intravenous Infusion—A Clinical Service Evaluation. The Pediatric Infectious Disease Journal, 40(2), 128–129 [PubMed: 33165272]
Vanderkooi 2005
Vanderkooi, O. G., Low, E. D., Green, K. et al. (2005). Predicting antimicrobial resistance in invasive pneumococcal infections, Clinical Infectious Diseases 40(9), 1288–1297 [PubMed: 15825031]

Appendices

Appendix D. Evidence tables

Evidence tables for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

No evidence was identified which was applicable to this review question.

Appendix E. Forest plots

Forest plots for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

No evidence was identified for this review question and so there are no forest plots.

Appendix F. GRADE tables

GRADE tables for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

No evidence was identified which was applicable to this review question.

Appendix G. Economic evidence study selection

Appendix H. Economic evidence tables

Economic evidence tables for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

No evidence was identified which was applicable to this review question.

Appendix I. Economic model

Economic model for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

No economic analysis was conducted for this review question.

Appendix J. Excluded studies

Excluded studies for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

Excluded effectiveness studies

The excluded studies table only lists the studies that were considered and then excluded at the full-text stage for this review (N=64) and not studies (N=128) that were considered and then excluded from the search at the full-text stage as per the PRISMA diagram in Appendix C for the other review questions in the same search.

Table 3

Excluded studies and reasons for their exclusion.

Excluded economic studies

No studies were identified which were applicable to this review question.

Appendix K. Research recommendations – full details

Research recommendations for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

No research recommendation was made for this review.

Final

Evidence review underpinning recommendations 1.6.4 to 1.6.9 and 1.6.16 in the NICE guideline

This evidence review was developed by NICE

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK604073PMID: 38829976

Table 1Summary of the protocol (PICO table)

Population	Younger infants (>28 days to ≤3 months of age) with suspected bacterial meningitis
Intervention	Antibiotic agent of interest: Amoxicillin, Ampicillin, Benzylpenicillin sodium, Cefotaxime, Ceftriaxone, Gentamicin In cases of severe beta-lactam allergy: Fluoroquinolones (all licensed in the UK), Chloramphenicol
Comparison	Stage 1 (all antibiotic agents of interest): Comparison: Amoxicillin or ampicillin plus cefotaxime or ceftriaxone vs amoxicillin or ampicillin plus gentamicin Amoxicillin or ampicillin plus cefotaxime or ceftriaxone vs benzylpenicillin sodium plus gentamicin Amoxicillin or ampicillin plus gentamicin vs benzylpencillin sodium plus gentamicin Amoxicillin or ampicillin plus gentamicin vs cefotaxime or ceftriaxone alone Benzylpenicillin sodium plus gentamicin vs cefotaxime or ceftriaxone alone Amoxicillin or ampicillin plus cefotaxime or ceftriaxone vs cefotaxime or ceftriaxone alone In cases of severe beta-lactam allergy: Chloramphenicol vs fluoroquinolones Stage 2 (antibiotic agents identified during stage 1 as most effective/for use where there are contraindications) Comparisons: Antibiotic agent A – Dose A vs Antibiotic agent A – Dose B Antibiotic agent A – Duration of administration A vs Antibiotic agent A – Duration of administration B Antibiotic agent A – Short infusion vs Antibiotic agent A – Extended infusion
Outcome	Critical All-cause mortality (measured up to 1 year after discharge) Any long-term neurological impairment (defined as any motor deficits, sensory deficits [excluding hearing impairment], cognitive deficits, or behavioural deficits; measured from discharge up to 1 year after discharge) Severe developmental delay (defined as score of >2 SD below normal on validated assessment scales, or MDI or PDI <70 on Bayleys assessment scale, or inability to assign a score due to cerebral palsy or severity of cognitive delay; measured at the oldest age reported unless there is substantially more data available at a younger age) Important Diagnosis of epilepsy or occurrence of seizures during hospitalisation Hearing impairment (defined as any level of hearing impairment; measured from discharge up to 1 year after discharge) Functional impairment (measured by any validated scale at any time point) Serious intervention-related adverse effects leading to death, disability or prolonged hospitalisation or that are life threatening or otherwise considered medically significant *For infants and children below school-age, cognitive and behavioural deficits will be assessed at school-age.

: MDI: mental development index; PDI: psychomotor development index; SD: standard deviation

Table 3Excluded studies and reasons for their exclusion

Study	Code [Reason]
(1993) Long-acting chloramphenicol for bacterial meningitis. Bulletin of the World Health Organization 71(1): 117–8, 123 [PMC free article: PMC2393436] [PubMed: 8440031]	- Study design does not meet inclusion criteria
Anonymous (1998) Antimicrobial therapy in the management of bacterial meningitis. WHO Drug Information 12(2): 70–72	- Study design does not meet inclusion criteria
Anonymous (1990) Ceftriaxone in the treatment of meningitis, gonococcal infections and other serious bacterial infections. Infectious Diseases and Immunization Committee, Canadian Paediatric Society. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne 142(5): 450–2 [PMC free article: PMC1451660] [PubMed: 2302641]	- Study design does not meet inclusion criteria
Anonymous (1986) Initial antibiotic treatment of bacterial meningitis in children. Infectious Diseases and Immunization Committee, Canadian Paediatric Society. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne 135(10): 1085–6 [PMC free article: PMC1491791] [PubMed: 3768819]	- Study design does not meet inclusion criteria
Anonymous (1997) Therapy for children with invasive pneumococcal infections. American Academy of Pediatrics Committee on Infectious Diseases. Pediatrics 99(2): 289–99 [PubMed: 9024464]	- Study design does not meet inclusion criteria
Anonymous (1995) Meropenem: A new carbapenem with potential for treating bacterial meningitis. Drugs and Therapy Perspectives 6(10): 1–5	- Study design does not meet inclusion criteria
Anonymous (1988) American Academy of Pediatrics Committee on Infectious Diseases: Treatment of bacterial meningitis. Pediatrics 81(6): 904–907 [PubMed: 3368290]	- Study design does not meet inclusion criteria
Anonymous (2010) Initiate appropriate antibacterial and adjunctive therapies when treating bacterial meningitis. Drugs and Therapy Perspectives 26(8): 19–22	- Study design does not meet inclusion criteria
Anttila, M., Anttolainen, I., Ellmén, J. et al. (1991) (Antibiotics for bacterial meningitis in children - results of a Finnish multicentre trial). Duodecim; laaketieteellinen aikakauskirja 107: 149–157 [PubMed: 1364751]	- Non-English language article
Anttila, M., Anttolainen, I., Ellmén, J. et al. (1991) Antibiotic treatment of bacterial meningitis in children--results from a Finnish multicenter study. Duodecim; laaketieteellinen aikakauskirja 107(3): 149–157 [PubMed: 1364751]	- Non-English language article
Aronoff, S. C., Reed, M. D., O’Brien, C. A. et al. (1984) Comparison of the efficacy and safety of ceftriaxone to ampicillin/chloramphenicol in the treatment of childhood meningitis. Journal of antimicrobial chemotherapy 13(2): 143–151 [PubMed: 6323376]	- Study included in systematic review – Prasad 2007 (included in evidence review 3.3b)
Barson, W. J., Miller, M. A., Brady, M. T. et al. (1985) Prospective comparative trial of ceftriaxone vs. conventional therapy for treatment of bacterial meningitis in children. Pediatric infectious disease 4(4): 362–368 [PubMed: 3895175]	- Study included in systematic review – Prasad 2007(included in evidence review 3.3b)
Bass, J. W.; Person, D. A.; Fonseca, R. J. (1990) Cefuroxime versus ceftriaxone for bacterial meningitis (I). Journal of pediatrics 116(3): 488 [PubMed: 2308044]	- Study design does not meet inclusion criteria
Begue, P., Astruc, J., Francois, P. et al. (1998) Comparison of ceftriaxone and cefotaxime in severe pediatric bacterial infection: a multicentric study. Medecine ET maladies infectieuses 28(4): 300–306	- Non-English language article
Bijlsma, Merijn W., Brouwer, Matthijs C., Kasanmoentalib, E. Soemirien et al. (2016) Community-acquired bacterial meningitis in adults in the Netherlands, 2006-14: a prospective cohort study. The Lancet. Infectious diseases 16(3): 339–47 [PubMed: 26652862]	- Study design does not meet inclusion criteria
Bilal, Ali, Taha, Muhamed-Kheir, Caeymaex, Laurence et al. (2016) Neonatal Meningococcal Meningitis In France From 2001 To 2013. The Pediatric infectious disease journal 35(11): 1270–1272 [PubMed: 27753774]	- No comparison of interest for review
Bingen, Edouard, Levy, Corinne, de la Rocque, France et al. (2005) Bacterial meningitis in children: a French prospective study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 41(7): 1059–63 [PubMed: 16142676]	- No comparison of interest for review
Bulloch, B.; Craig, W. R.; Klassen, T. P. (1997) The use of antibiotics to prevent serious sequelae in children at risk for occult bacteremia: a meta-analysis. Academic Emergency Medicine 4(7): 679–683 [PubMed: 9223690]	- Population does not meet inclusion criteria
Cantey, Joseph B., Lopez-Medina, Eduardo, Nguyen, Sean et al. (2015) Empiric Antibiotics for Serious Bacterial Infection in Young Infants: Opportunities for Stewardship. Pediatric emergency care 31(8): 568–71 [PubMed: 25822235]	- Population does not meet inclusion criteria
Chaudhary, M.; Shrivastava, S. M.; Sehgal, R. (2008) Efficacy and safety study of fixed-dose combination of ceftriaxone-vancomycin injection in patients with various infections. Current drug safety 3(1): 82–85 [PubMed: 18690985]	- Population does not meet inclusion criteria
Chowdhary, G.; Dutta, S.; Narang, A. (2006) Randomized controlled trial of 7-Day vs. 14-Day antibiotics for neonatal sepsis. Journal of tropical pediatrics 52(6): 427–32 [PubMed: 17030532]	- Population does not meet inclusion criteria
Coon, Eric R., Srivastava, Raj, Stoddard, Greg et al. (2018) Shortened IV Antibiotic Course for Uncomplicated, Late-Onset Group B Streptococcal Bacteremia. Pediatrics 142(5) [PubMed: 30309887]	- Population does not meet inclusion criteria
de Louvois, J.; Mulhall, A.; Hurley, R. (1982) Cefuroxime in the treatment of neonates. Archives of disease in childhood 57(1): 59–62 [PMC free article: PMC2863279] [PubMed: 7065695]	- No comparison of interest for review
del Rio, M. A., Chrane, D., Shelton, S. et al. (1983) Ceftriaxone versus ampicillin and chloramphenicol for treatment of bacterial meningitis in children. Lancet (london, england) 1(8336): 1241–1244 [PubMed: 6134039]	- Study included in systematic review – Prasad 2007 (included in evidence review 3.3b)
Donnelly, P. C., Sutich, R. M., Easton, R. et al. (2017) Ceftriaxone-Associated Biliary and Cardiopulmonary Adverse Events in Neonates: A Systematic Review of the Literature. Pediatric Drugs 19(1): 21–34 [PubMed: 27718120]	- Population does not meet inclusion criteria
Feldman, E. A., McCulloh, R. J., Myers, A. L. et al. (2017) Empiric antibiotic use and susceptibility in infants with bacterial infections: A multicenter retrospective cohort study. Hospital Pediatrics 7(8): 427–435 [PMC free article: PMC5525435] [PubMed: 28729240]	- No outcomes of interest for review
Furyk, J. S.; Swann, O.; Molyneux, E. (2011) Systematic review: neonatal meningitis in the developing world. Tropical medicine & international health : TM & IH 16(6): 672–9 [PubMed: 21395927]	- No comparison of interest for review
Haffejee, I. E. (1984) A therapeutic trial of cefotaxime versus penicillin-gentamicin for severe infections in children. Journal of antimicrobial chemotherapy 14supplb: 147–152 [PubMed: 6094434]	- Population does not meet inclusion criteria
Haffejee, I. E. (1988) Cefotaxime versus penicillin-chloramphenicol in purulent meningitis: a controlled single-blind clinical trial. Annals of tropical paediatrics 8(4): 225–9 [PubMed: 2467608]	- Study included in systematic review – Prasad 2007 (included in evidence review 3.3b)
Hodgson, Kate Alison, Lim, Ruth, Huynh, Julie et al. (2022) Outpatient parenteral antimicrobial therapy: how young is too young?. Archives of disease in childhood [PubMed: 35537826]	- Study design does not meet inclusion criteria
Johansson, O.; Cronberg, S.; Hoffstedt, B. (1982) Cefuroxime versus ampicillin and chloramphenicol for the treatment of bacterial meningitis. Report from a Swedish study group. Lancet 1(8267): 295–299 [PubMed: 6120310]	- Population does not meet inclusion criteria
Joubrel, C., Tazi, A., Six, A. et al. (2015) Group B streptococcus neonatal invasive infections, France 2007-2012. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 21(10): 910–6 [PubMed: 26055414]	- Study design does not meet inclusion criteria
Karageorgopoulos, D. E., Valkimadi, P. E., Kapaskelis, A. et al. (2009) Short versus long duration of antibiotic therapy for bacterial meningitis: a meta-analysis of randomised controlled trials in children. Archives of Disease in Childhood 94(8): 607–614 [PubMed: 19628879]	- Population does not meet inclusion criteria
Kasiakou, S. K., Sermaides, G. J., Michalopoulos, A. et al. (2005) Continuous versus intermittent intravenous administration of antibiotics: A meta-analysis of randomised controlled trials. Lancet Infectious Diseases 5(9): 581–589 [PubMed: 16122681]	- Population does not meet inclusion criteria
Kecmanovic, M.; Pavlovic, M.; Kostic, A. (1982) Cefotaxime in the treatment of suppurative meningitis. Chemioterapia 1(4suppl): 85	- Study design does not meet inclusion criteria
Klugman, K. P. and Dagan, R. (1995) Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis. Meropenem Meningitis Study Group. Antimicrobial agents and chemotherapy 39(5): 1140–1146 [PMC free article: PMC162697] [PubMed: 7625802]	- Population does not meet inclusion criteria
Korbila, I. P., Tansarli, G. S., Karageorgopoulos, D. E. et al. (2013) Extended or continuous versus short-term intravenous infusion of cephalosporins: A meta-analysis. Expert Review of Anti-Infective Therapy 11(6): 585–595 [PubMed: 23750730]	- Population does not meet inclusion criteria
Levine, D. P.; McNeil, P.; Lerner, S. A. (1989) Randomized, double-blind comparative study of intravenous ciprofloxacin versus ceftazidime in the treatment of serious infections. American journal of medicine 87(5a): 160S–163S [PubMed: 2686416]	- Population does not meet inclusion criteria
Madson, L. and Grose, C. (1990) Ceftriaxone vs cefotaxime for treatment of Haemophilus influenzae meningitis (I). Pediatrics 85(4): 622–623 [PubMed: 2314980]	- Study design does not meet inclusion criteria
Marget, W.; Belohradsky, B. H.; Roos, R. (1980) Guidelines for adequate chemotherapeutic dosage in newborns and infants with septicaemia and meningitis. Infection suppl1: 82–6 [PubMed: 7399719]	- Study design does not meet inclusion criteria
Martin, E., Hohl, P., Guggi, T. et al. (1990) Short course single daily ceftriaxone monotherapy for acute bacterial meningitis in children: results of a Swiss multicenter study. Part I: clinical results. Infection 18(2): 70–77 [PubMed: 2185156]	- Population does not meet inclusion criteria
Mathur, N. B.; Kharod, P.; Kumar, S. (2015) Evaluation of duration of antibiotic therapy in neonatal bacterial meningitis: a randomized controlled trial. Journal of tropical pediatrics 61(2): 119–125 [PubMed: 25681965]	- Population does not meet inclusion criteria
McCracken Jr, G. H. (1986) Aminoglycoside toxicity in infants and children. American Journal of Medicine 80(6b): 172–178 [PubMed: 3524215]	- Study design does not meet inclusion criteria
McGee, Lesley, Chochua, Sopio, Li, Zhongya et al. (2020) Multistate, population-based distributions of candidate vaccine targets, clonal complexes, and resistance features of invasive Group B Streptococci within the US: 2015-2017. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America [PMC free article: PMC8071603] [PubMed: 32060499]	- No comparison of interest for review
McGill, F., Heyderman, R. S., Michael, B. D. et al. (2016) The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults. The Journal of infection 72(4): 405–38 [PubMed: 26845731]	- Study design does not meet inclusion criteria
Molyneux, E. M., Dube, Q., Banda, F. M. et al. (2017) The Treatment of Possible Severe Infection in Infants: an Open Randomized Safety Trial of Parenteral Benzylpenicillin and Gentamicin Versus Ceftriaxone in Infants <60 days of Age in Malawi. Pediatric infectious disease journal 36(12): e328–e333 [PMC free article: PMC5466153] [PubMed: 28263245]	- Population does not meet inclusion criteria
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Okike, I. O., Awofisayo, A., Adak, B. et al. (2015) Empirical antibiotic cover for Listeria monocytogenes infection beyond the neonatal period: A time for change?. Archives of Disease in Childhood 100(5): 423–425 [PubMed: 25628458]	- Study design does not meet inclusion criteria
Onakpoya, Igho J., Walker, A. Sarah, Tan, Pui S. et al. (2018) Overview of systematic reviews assessing the evidence for shorter versus longer duration antibiotic treatment for bacterial infections in secondary care. PloS one 13(3): e0194858 [PMC free article: PMC5874047] [PubMed: 29590188]	- Insufficient presentation of results
Pintado, Vicente, Cabellos, Carmen, Moreno, Santiago et al. (2003) Enterococcal meningitis: a clinical study of 39 cases and review of the literature. Medicine 82(5): 346–64 [PubMed: 14530784]	- Study design does not meet inclusion criteria
Romain, O. (2017) Antibiotherapy for early-onset neonatal bacterial infections in newborn borns > 34 week’s gestation. Archives de Pediatrie 24(supplement3): S24–S28	- Non-English language article
Schaad, U. B. (1984) The cephalosporin compounds in severe neonatal infection. European journal of pediatrics 141(3): 143–6 [PubMed: 6321189]	- Study design does not meet inclusion criteria
Schaad, U. B., Suter, S., Gianella-Borradori, A. et al. (1990) A comparison of ceftriaxone and cefuroxime for the treatment of bacterial meningitis in children. New England journal of medicine 322(3): 141–147 [PubMed: 2403654]	- Population does not meet inclusion criteria
Scholz, H., Hofmann, T., Noack, R. et al. (1998) Prospective comparison of ceftriaxone and cefotaxime for the short-term treatment of bacterial meningitis in children. Chemotherapy 44(2): 142–147 [PubMed: 9551246]	- Population does not meet inclusion criteria
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Tetanye, E., Yondo, D., Bernard-Bonnin, A. C. et al. (1990) Initial treatment of bacterial meningitis in Yaounde, Cameroon: theoretical benefits of the ampicillin-chloramphenicol combination versus chloramphenicol alone. Annals of tropical paediatrics 10(3): 285–291 [PubMed: 1703746]	- Population does not meet inclusion criteria
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van de Beek, D., Cabellos, C., Dzupova, O. et al. (2016) ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 22suppl3: S37–62 [PubMed: 27062097]	- Study design does not meet inclusion criteria
Van Reempts, P. J., Van Overmeire, B., Mahieu, L. M. et al. (1995) Clinical experience with ceftriaxone treatment in the neonate. Chemotherapy 41(4): 316–22 [PubMed: 7555213]	- Population does not meet inclusion criteria
Watanakunakorn, C., Greifenstein, A., Stroh, K. et al. (1993) Pneumococcal bacteremia in three community teaching hospitals from 1980 to 1989. Chest 103(4): 1152–6 [PubMed: 8131456]	- Population does not meet inclusion criteria
Weiss, D. and Glaser, J. H. (1990) Ceftriaxone versus cefuroxime for treatment of bacterial meningitis. Journal of pediatrics 116(3): 492 [PubMed: 2308045]	- Study design does not meet inclusion criteria
Wintenberger, C., Guery, B., Bonnet, E. et al. (2017) Proposal for shorter antibiotic therapies. Medecine et maladies infectieuses 47(2): 92–141 [PubMed: 28279491]	- Study design does not meet inclusion criteria
Woods, C. R. (2018) Uncomplicated late-onset group b streptococcal bacteremia: Can we do less than 10 days IV?. Pediatrics 142(5): e20182623 [PubMed: 30309888]	- Study design does not meet inclusion criteria
Zhao, Zhi, Hua, Xueying, Yu, Jialin et al. (2019) Duration of empirical therapy in neonatal bacterial meningitis with third generation cephalosporin: a multicenter retrospective study. Archives of medical science : AMS 15(6): 1482–1489 [PMC free article: PMC6855170] [PubMed: 31749877]	- Population does not meet inclusion criteria

Evidence reviews for antibiotics for bacterial meningitis before or in the absence of identifying causative infecting organism in younger infants

Antibiotics for bacterial meningitis before or in the absence of identifying causative infecting organism in younger infants

Review question

Introduction

Summary of the protocol

Table 1

Methods and process

Effectiveness evidence

Included studies

Excluded studies

Summary of included studies

Summary of the evidence

Economic evidence

Included studies

Economic model

The committee’s discussion and interpretation of the evidence

The outcomes that matter most

The quality of the evidence

Benefits and harms

Cost effectiveness and resource use

Recommendations supported by this evidence review

References – included studies

Effectiveness

Economic

Other

Appendices

Appendix A. Review protocols

Appendix B. Literature search strategies

Appendix C. Effectiveness evidence study selection

Appendix D. Evidence tables

Evidence tables for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

Appendix E. Forest plots

Forest plots for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

Appendix F. GRADE tables

GRADE tables for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

Appendix G. Economic evidence study selection

Appendix H. Economic evidence tables

Economic evidence tables for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

Appendix I. Economic model

Economic model for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

Appendix J. Excluded studies

Excluded studies for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

Excluded effectiveness studies

Table 3

Excluded economic studies

Appendix K. Research recommendations – full details

Research recommendations for review question: What antibiotic treatment regimens are effective in treating suspected bacterial meningitis in younger infants before identifying the causative infecting organism, or in the absence of identifying the causative infecting organism?

Table 1Summary of the protocol (PICO table)

Table 3Excluded studies and reasons for their exclusion