Effectiveness of Eight Antibiotic Combinations for Treating Newborn Sepsis — Evidence Review

A new multicountry trial has identified eight promising antibiotic combinations, including older drugs not previously used for neonatal sepsis in Africa, as safe and potentially effective treatments for newborns with life-threatening infections. Related studies generally support the need for new treatment strategies for neonatal sepsis due to rising antimicrobial resistance, though there is ongoing debate over optimal regimens and the role of combination therapy (1, 2, 4).

• The study’s focus on repurposing older antibiotics like fosfomycin and flomoxef aligns with calls in the literature for investigating both older and novel agents to address multidrug-resistant (MDR) Gram-negative neonatal sepsis, particularly in low- and middle-income countries where resistance to standard therapies is high (2, 4).
• Existing meta-analyses and randomized controlled trials suggest that while combination therapies may not always outperform monotherapies in general sepsis populations, their use in high-risk infants—such as those with neonatal sepsis and high mortality risk—may be justified; however, safety concerns, especially nephrotoxicity, must be carefully weighed (6, 7, 10).
• Studies consistently highlight the urgent need for improved surveillance, rapid diagnostics, and evidence-based guidelines for second-line or alternative antibiotics, supporting the new trial’s aim to inform global and national policy on neonatal sepsis management (1, 4, 8).

Study Overview and Key Findings

Neonatal sepsis remains a leading cause of infant mortality, particularly in Africa and Asia, with existing first-line antibiotics losing efficacy due to widespread antimicrobial resistance. The NeoSep1 trial, coordinated by the Global Antibiotic Research and Development Partnership (GARDP), is significant because it systematically evaluates combinations of both conventional and repurposed antibiotics—including older agents like fosfomycin and flomoxef—for treating neonatal sepsis in diverse, resource-limited settings. Uniquely, the study not only assesses clinical efficacy and safety but also aims to generate evidence to update World Health Organization (WHO) guidelines and reduce unnecessary antibiotic exposure in this vulnerable population.

Property	Value
Study Year	2023
Organization	Global Antibiotic Research and Development Partnership, Kemri-Wellcome Trust Research Programme
Authors	Sally Ellis, Christina Obiero, Alexander Makazi, Robert Mwakesi
Population	Newborns with sepsis
Sample Size	3,000 babies
Methods	Randomized Controlled Trial (RCT)
Outcome	Effectiveness and safety of antibiotic combinations
Results	Eight antibiotic combinations were narrowed down for testing.

Literature Review: Related Studies

We searched the Consensus paper database, which contains over 200 million research papers, for studies relevant to antibiotic resistance and neonatal sepsis. The following queries were used:

1. antibiotic resistance sepsis treatment babies
2. old antibiotics effectiveness combinations sepsis
3. clinical trials antibiotic combinations infants

Topic	Key Findings
What is the current effectiveness of standard antibiotics for neonatal sepsis?	- WHO-recommended regimens (penicillin/gentamicin) are increasingly compromised by resistance, especially in LMICs, and third-generation cephalosporins offer no substantial advantage (1, 8). - High rates of resistance and mortality are reported with standard empiric therapies, highlighting the need for new or alternative regimens (2, 5).
Do alternative or older antibiotics have a role in treating MDR neonatal sepsis?	- Older antibiotics like fosfomycin and colistin are being reconsidered for MDR Gram-negative neonatal sepsis, but data on safety and dosing are limited; strategic trials are urgently needed (4). - Repurposing older drugs is supported as a strategy in settings with high resistance to first-line agents (4, 2).
Does combination antibiotic therapy improve outcomes over monotherapy in sepsis?	- Combination therapy may benefit high-risk or critically ill patients but shows no all-cause mortality advantage in general sepsis populations; risk of nephrotoxicity increases with combination regimens (6, 7, 10). - Mortality reduction is noted when combining antibiotics with different mechanisms of action in severe sepsis (9).
What are the risks of antibiotic resistance and microbiome disruption in neonates?	- Early-life antibiotic exposure alters the gut microbiome and increases resistance gene carriage, with broader-spectrum regimens causing more pronounced effects (11). - Rational and minimized antibiotic use is critical to reduce adverse outcomes and the spread of resistance (5, 8).

What is the current effectiveness of standard antibiotics for neonatal sepsis?

Multiple studies indicate that the effectiveness of standard WHO-recommended antibiotics (penicillin or ampicillin plus gentamicin) is being undermined by rising rates of antimicrobial resistance, particularly in low- and middle-income countries. The new trial’s rationale is directly informed by these findings, as treatment failures and mortality remain high, necessitating the search for better regimens.

• High resistance rates to first-line therapies are widely reported, especially against Klebsiella, E. coli, and other Gram-negative pathogens (2, 5).
• Meta-analyses show that third-generation cephalosporins do not outperform penicillin/gentamicin in neonatal sepsis and are also subject to resistance (8).
• Current guidelines remain based on available evidence, but there is clear acknowledgment in the literature that new strategies are needed as resistance patterns worsen (1, 8).
• The new study’s goal to update treatment options is strongly supported by the observed gaps in efficacy of existing regimens (1, 2, 8).

Do alternative or older antibiotics have a role in treating MDR neonatal sepsis?

The literature emphasizes the importance of considering older antibiotics—such as fosfomycin and colistin—which may be effective against multidrug-resistant pathogens but lack robust neonatal data. The NeoSep1 trial’s inclusion of older drugs like fosfomycin and flomoxef builds upon these calls for rigorous trials.

• There is a pressing need to evaluate older antibiotics due to the spread of resistance to standard and even newer drugs (4).
• Strategic and regulatory trials of both older and new antibiotics are highlighted as necessary to improve neonatal sepsis outcomes (4).
• Observational studies support the repurposing of older drugs in high-resistance settings, especially where novel agents are unavailable or unaffordable (2, 4).
• Safety and dosing data for neonates are limited, making the current trial’s focus on these parameters particularly significant (4).

Does combination antibiotic therapy improve outcomes over monotherapy in sepsis?

Evidence on the benefits of combination antibiotic therapy is mixed, with meta-analyses showing little advantage over monotherapy for all patients but possible benefits in the most severely ill—such as neonates with high mortality risk—at the cost of increased toxicity. The NeoSep1 trial’s strategy of testing multiple combinations reflects this nuanced landscape.

• Combination therapy may reduce mortality in high-risk or septic shock patients, but not in low-risk populations (6).
• Meta-analyses caution against routine use of aminoglycoside-beta-lactam combinations due to higher nephrotoxicity without clear survival benefit (7, 10).
• Combining antibiotics with different mechanisms can lower mortality in severe sepsis (9).
• The trial’s approach to stratify regimens for safety and efficacy in neonates aligns with these findings, emphasizing individualized therapy (6, 7, 9, 10).

What are the risks of antibiotic resistance and microbiome disruption in neonates?

Recent randomized trials show that early-life exposure to broad-spectrum antibiotics can significantly disturb the developing gut microbiome and promote antimicrobial resistance gene carriage, emphasizing the need for judicious selection and use of antibiotics in this population.

• The magnitude of microbiome disruption varies by antibiotic regimen, with broader-spectrum combinations causing greater shifts (11).
• Reducing unnecessary or broad-spectrum antibiotic use may mitigate adverse effects on the microbiome and slow resistance development (5, 8, 11).
• These findings reinforce the new study’s goal to optimize and minimize antibiotic exposure in neonates (11).
• The need for rapid diagnostics to guide targeted therapy and avoid overuse is highlighted throughout the literature (5, 8, 11).

Future Research Questions

While the NeoSep1 trial advances the evidence base for treating neonatal sepsis amid rising antimicrobial resistance, several important questions remain. Future research should address optimal duration and dosing for older antibiotics in neonates, the long-term safety of new combinational regimens, rapid diagnostics for targeted therapy, and the broader ecological impacts of antibiotic use in newborns.

Research Question	Relevance
What are the long-term safety and developmental outcomes in infants treated with fosfomycin-flomoxef or other older antibiotics?	Long-term safety data are lacking for older antibiotics in neonates, yet their use is increasing in response to MDR pathogens (4). Monitoring for developmental or organ-specific effects is critical.
How can rapid diagnostic tools be developed and implemented to guide targeted antibiotic therapy in neonatal sepsis?	Delays in identifying causative pathogens hinder timely, appropriate therapy and contribute to resistance and mortality (5, 8). Rapid diagnostics could transform sepsis management.
What is the optimal duration and dosing for older antibiotics like fosfomycin in neonates with sepsis?	Dosing and duration data for repurposed antibiotics in neonates are scarce, necessitating further pharmacological and clinical studies (4, 2).
How do different antibiotic regimens affect the neonatal gut microbiome and resistance gene profiles over time?	Antibiotic-induced changes to the microbiome and resistome may have lasting health implications, as recent studies have begun to document (11).
What are the cost-effectiveness and accessibility impacts of introducing new antibiotic combinations in resource-limited settings?	Assessing the economic and logistical feasibility of new regimens is essential for real-world adoption, especially in low-resource environments facing the highest burden (4, 5).