PREreview of Identification of potential novel combination antibiotic regimens based on drug-susceptibility and genetic diversity of Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries

This review reflects comments and contributions from Femi Arogundade.

The study conducted a prospective observational clinical investigation of neonatal sepsis across 19 hospitals in 11 low- and middle-income countries, identifying Gram-negative bacteria, particularly Klebsiella pneumoniae and Acinetobacter baumannii, as prevalent causative agents. The findings underscore the alarming rates of antimicrobial resistance, particularly the widespread occurrence of extended-spectrum beta-lactamases (ESBLs), and highlight the urgent need for novel treatment strategies. The evaluation of three antibiotic combinations, fosfomycin-flomoxef, fosfomycin-amikacin, and flomoxef-fosfomycin, reveals promising activity against ESBL-producing strains, suggesting potential alternatives for neonatal sepsis treatment in the face of multidrug resistance. Despite the valuable insights, the study acknowledges limitations, such as varying sample sizes and blood culture positivity rates across sites, emphasizing the importance of future research to address these challenges in low-resource settings.

General Comments:

Positive Aspects of the Paper

• The study spans 19 hospitals across 11 low- and middle-income countries, providing a comprehensive and diverse representation of neonatal sepsis cases.

• The study focuses on a crucial concern: neonatal sepsis stemming from Gram-negative bacteria in environments where managing this issue poses significant difficulties.

• The study successfully identifies Klebsiella pneumoniae and Acinetobacter baumannii as the most frequently isolated Gram-negative bacteria, offering valuable insights into the epidemiology of neonatal sepsis.

• The paper contributes important data on antimicrobial resistance patterns, highlighting the widespread occurrence of extended-spectrum beta-lactamases (ESBLs) and the need for alternative treatment strategies.

• The study proposes and evaluates three novel antibiotic combinations (fosfomycin-flomoxef, fosfomycin-amikacin, flomoxef-fosfomycin) that demonstrate high activity against multidrug-resistant strains, suggesting potential alternative therapeutic options.

• The paper transparently acknowledges limitations, such as variations in blood culture positivity rates and potential biases in sample representation, promoting a realistic interpretation of the study's findings.

• The study appropriately concludes with a call for further evaluation of the proposed antibiotic combinations in clinical trials, demonstrating a commitment to translating findings into actionable strategies for neonatal sepsis treatment.

Minor Comments:

• Explain the statement: "The NeoOBS study showed a wide variety of bacterial species as a cause of neonatal sepsis, many of which carried multiple resistance genes." Provide examples of specific bacterial species and associated resistance genes to enhance the clarity of this statement.

• Add clarification to the conclusion: "The three novel antibiotic combinations, fosfomycin-flomoxef, fosfomycin-amikacin, and flomoxef-fosfomycin showed high activity, especially against ESBL-producing E. coli and Klebsiella pneumoniae isolates." Specify the observed activity levels and discuss how these combinations address the challenges posed by ESBL-producing strains.

• Clarify the statement: "Susceptibility rates to flomoxef (71%) and amikacin (70%) were comparable to those observed for meropenem (75%) in the subset of 108 isolates with available MIC results." Elaborate on the clinical implications of these susceptibility rates and their relevance to neonatal sepsis treatment.

Major Comments:

• Detailed characterization of bacterial isolates through Whole Genome Sequencing (WGS) and subsequent analyses, including MLST and cgMLST, strengthens the identification of genetic diversity and resistance mechanisms.

• The in vitro susceptibility testing of novel antibiotic combinations provides valuable insights, but the extrapolation to clinical efficacy requires further investigation through clinical trials.

• The comprehensive presentation of data, including resistance profiles, genetic diversity, and the evaluation of novel antibiotic combinations, supports the study's conclusions.

• The microbiological protocol for the collection, storage, and shipment of isolates is mentioned briefly. Could the paper provide more detailed information on this protocol, considering its crucial role in maintaining the integrity of bacterial isolates?

• Clarify the criteria for clinically suspected sepsis in infants under 60 days of age. Was a standardized definition employed across all participating sites?

• The exclusion of bacterial isolates from certain sites in India and China raises questions about the representativeness of the study. Could the authors provide more context or rationale for this exclusion?

• Provide details on the HFIM model and checkerboard assays for determining novel combination breakpoint thresholds. How were these thresholds validated, and what are the potential limitations?

• The study includes isolates from only 13 out of 19 hospitals mentioned in the study setting. The reason for not obtaining bacterial isolates from the remaining 6 hospitals should be clarified to ensure the sample's representativeness.

• The criteria for selecting isolates for inclusion in the microbiology study seem reasonable, but the rationale for choosing the patient's first clinical isolate in case of mixed infections should be explicitly justified. Additionally, the definition of "different genetic profiles" needs clarification.

• The uneven distribution of multi-drug-resistant A. baumannii at specific sites is intriguing. Are there site-specific factors influencing the prevalence of this pathogen, and what implications does this have for infection control measures?

• Based on the findings, what recommendations or strategies can be suggested for antimicrobial resistance control in neonatal units, especially in settings with resource constraints?

Suggestions for Future Studies:

• Conduct longitudinal studies to observe changes in resistance patterns over time. This would provide insights into the dynamic nature of antimicrobial resistance and help in identifying emerging trends.

• Incorporate an analysis of clinical outcomes associated with different resistance patterns. Understanding the impact of specific resistance mechanisms on patient outcomes could guide treatment strategies and improve neonatal care.

• Explore genomic epidemiology in more detail. Investigate the genetic relatedness of isolates within and between sites to uncover potential transmission patterns and the spread of resistance genes.

• Include investigations into host factors and immune responses. Understanding how host factors contribute to susceptibility and the effectiveness of antibiotic regimens can inform personalized treatment approaches.

• Consider studies that evaluate the impact of interventions aimed at reducing neonatal sepsis and antimicrobial resistance. This could include interventions such as improved hygiene practices, antibiotic stewardship programs, and vaccination strategies.

• Translate research findings into actionable public health policy recommendations. Work towards influencing policies that address the prevention and management of neonatal sepsis, with a focus on reducing antimicrobial resistance.

Competing interests

The author declares that they have no competing interests.