Editor’s Note: Neonatal sepsis refers to the systemic inflammatory response syndrome caused by various pathogens in newborns, ranking as the third leading cause of neonatal mortality globally. Meropenem is one of the most widely used broad-spectrum antibiotics in the treatment of neonatal sepsis. However, its irrational use has led to an increasingly serious problem of bacterial multidrug resistance. The Clinical Practice Guidelines for the Use of Meropenem in Treating Neonatal Sepsis (2024 Edition) provide 12 recommendations addressing 9 clinical issues, covering the timing of meropenem use, recommended dosage, prolonged infusion, monitoring and assessment, antibiotic adjustment strategies, treatment duration, and therapeutic strategies for carbapenem-resistant Enterobacteriaceae infections. These guidelines aim to provide evidence-based recommendations for the rational use of meropenem in neonatal sepsis patients. Professor Xiaomei Tong from the Department of Pediatrics at Peking University Third Hospital presented a detailed interpretation of the guidelines at the recent Fourth National Congress of the Chinese Medical Association for Bacterial and Fungal Infections (BISC 2024).

Current Use of Antibiotics in Neonatal Sepsis

Early and rational use of antibiotics is crucial in reducing the mortality rate of severe infections. Gram-negative bacilli are the main pathogens causing neonatal mortality, with different Gram-negative bacteria leading to varying mortality rates in neonatal sepsis.

Severe drug-resistant Gram-negative bacillus septicemia often requires treatment with carbapenems. Carbapenems are commonly used for anti-infective therapy in neonates with severe sepsis, characterized by a broad antibacterial spectrum, stability against most β-lactamases, resistance to hydrolysis, and relatively fewer adverse reactions. Among them, meropenem is the most widely used in neonatal patients with severe infections. However, as a broad-spectrum antibiotic classified for special use, its irrational use has led to an increasingly serious problem of bacterial multidrug resistance.

The main blind spots in the use of antibiotics in neonates mainly stem from the lack of sufficient evidence-based data to guide clinical practice, resulting in antibiotic over-prescription and unrestricted use. Physicians often face challenges in selecting antibiotics, determining bacterial resistance, managing pharmacokinetics and pharmacodynamics, and monitoring adverse reactions and safety due to limited knowledge. Furthermore, the lack of guidelines for the specific use of certain antibiotics also leads to a lack of clear guidance for physicians in medication.

In current empirical antibiotic therapy, antibiotics are typically initiated in high-risk neonates before blood culture sensitivity results are available, a practice known as “empirical antibiotic therapy.” However, this approach poses significant problems. Most neonates admitted to neonatal intensive care units (NICUs) receive empirical antibiotic therapy. However, it is concerning that among cases receiving antibiotic therapy, the ratio of uninfected to blood culture-positive neonates can be as high as 15-28:1. Although early initiation of empirical antibiotic therapy can reduce neonatal mortality for neonates with clinical symptoms of sepsis, overuse of antibiotics can lead to a range of adverse consequences, including organ damage, antibiotic-related diarrhea, drug allergies, and increased bacterial resistance.

Therefore, there is a need to optimize the strategies for antibiotic use in neonates.

Optimization of Antibiotic Management

In 1996, American scholars first proposed the concept of antibiotic stewardship, emphasizing the rational use of antibiotics through management measures. In 2013, Hyun et al. summarized the basic principles of pediatric antibiotic stewardship: 1. Who and when antibiotics should be administered; 2. Types of antibiotics; 3. Method of use; 4. Continuous monitoring of antibiotic use; 5. Strengthening professional education to gradually change clinical routine behavior through medical record review, prescription surveys, educational interventions, and outcome feedback, reducing the use of antibiotics and shortening antibiotic courses. Antibiotic de-escalation (ADE) is a component of antibiotic stewardship (AMS) aimed at reducing exposure to broad-spectrum antibiotics. The Chinese Pediatric Critical Care Working Group of the Chinese Medical Association issued several recommendations for the use of antibiotics in severe bacterial infections in pediatric intensive care units, proposing a process for antibiotic de-escalation therapy.

On February 27, 2017, the World Health Organization, in collaboration with the University of Tübingen in Germany, after in-depth research and cooperation, developed and published a list covering 12 key drug-resistant bacteria. Among them, carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Enterobacteriaceae producing extended-spectrum β-lactamases (ESBLs) were listed as first priority. The screening criteria for this list are quite strict, considering factors such as the frequency of bacterial resistance development, resistance to multiple antibiotics, mortality rates, occurrence rates of infections outside hospitals, and burdens on the healthcare system. Faced with this grim situation, the need for developing new antibiotics becomes particularly urgent.

The authoritative medical journal JAMA recently published a commentary emphasizing that the problem of antibiotic resistance has become a public health challenge that cannot be ignored. This problem not only seriously threatens human health but may even reverse many advances made in medical treatment over the past forty years. According to statistics, in the United States, infections caused by multidrug-resistant organisms (MDROs) lead to approximately 35,000 deaths each year and increase healthcare costs by a staggering $4.6 billion. Therefore, there is an urgent need to optimize existing treatment strategies, strengthen research on antibiotic resistance, and address this increasingly serious public health crisis.

Current Use of Meropenem in Neonates

A comprehensive retrospective cohort study was conducted in the United States on 5,566 infants treated with meropenem or imipenem/cilastatin in neonatal intensive care units (NICUs) between 1997 and 2010, showing a year-on-year increase in the use of meropenem. Meanwhile, NICUs in China are facing increasingly severe bacterial resistance issues. National multicenter data show that the resistance rates of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa to meropenem in NICUs are significantly higher than those in the United States and the general population in China. Especially for Klebsiella pneumoniae, the resistance rate to meropenem in NICUs is as high as 27.4%. Given this serious situation, strict control and optimization of carbapenem use in neonates are urgently needed.

The optimization of carbapenem use in clinical practice hinges on a deep understanding and application of pharmacokinetic (PK) and pharmacodynamic (PD) principles. PK quantitatively describes the dynamic changes in drug concentration in body fluids under dosing, including drug absorption, distribution, metabolism, and excretion. PD focuses on the therapeutic effects and possible adverse reactions of drugs on the body. By precisely analyzing PK/PD parameters, we can more accurately grasp the duration of antibacterial action of antibiotics in the body. Drug regimens developed based on this can effectively increase the clearance rate of pathogens, enhance clinical treatment effects, and help prevent the development of bacterial resistance.

However, when using meropenem in neonates, we face many challenges. Firstly, the stability issue of meropenem cannot be ignored. Studies have shown that a meropenem solution prepared at 25°C can degrade by 10% within 5 hours, and the degradation rate significantly increases with temperature. Therefore, it is not recommended to prolong the infusion duration excessively, and the recommended infusion time should be kept within 2-3 hours. Secondly, meropenem has good water solubility and is mainly excreted in its original form through the kidneys. When neonatal renal function is impaired, the drug’s half-life will be correspondingly prolonged, requiring full consideration of the drug’s changes in the body during prolonged infusion. Additionally, although extending the infusion time can increase the plasma PD targets, it may reduce drug concentrations in the cerebrospinal fluid and urine, which is particularly important when serious infections occur in other parts of the body.

Finally, off-label use is also a concern. Currently, there is still off-label use of carbapenems in infants under 3 months of age, including extended infusion of meropenem, which requires informed consent. During this process, ensuring the stability of the drug is crucial.

In summary, optimizing the clinical application of carbapenems in neonates requires comprehensive consideration of drug stability, water solubility, excretion characteristics, and PK/PD principles. Through scientific dosing regimens, the maximum therapeutic effects of drugs can be achieved, while simultaneously reducing the risks of adverse reactions and bacterial resistance.

Clinical Practice Guidelines for the Use of Meropenem in Treating Neonatal Sepsis (2024 Edition) Currently, there is a lack of professional guidance on the rational use of meropenem (MEM) for neonatal sepsis both domestically and internationally. Against this background, the research team conducted a retrospective cohort study at a single center for a period of 10 years, covering 12,047 discharged patients during the same period. Among them, the utilization rate of meropenem was 5.42%. After strict screening and assessment, 256 effective cases were finally included. Relying on the data accumulated in the early stage, the research team published systematic reviews and retrospective cohort studies, describing the efficacy and safety of prolonged infusion of meropenem in neonatal patients with severe infections. In addition, to gain a more comprehensive understanding of the opinions and experiences of domestic neonatologists regarding the use of meropenem, we distributed questionnaires to neonatologists from 31 provinces across the country, covering 21 clinical questions related to the use of meropenem, and successfully collected 1,501 valid questionnaires. Subsequent cross-sectional studies revealed the current practice and cognition status of pediatricians regarding the prolonged or continuous infusion of meropenem in severe infections.

Based on this foundation, the research team conducted in-depth research and referred to international guidelines for standard development criteria, organizing an authoritative expert team. Over a period of more than 2 years, the team jointly formulated the “Clinical Practice Guidelines for the Use of Meropenem in Treating Neonatal Sepsis (2024 Edition)” (hereinafter referred to as this guideline). The Evidence-Based Medicine Center of Lanzhou University, the WHO Collaborating Center for Guideline Implementation and Knowledge Translation, and the Drug Evaluation Center of Peking University Medical College provided methodological support, with Peking University Third Hospital serving as the secretariat. The aim is to provide guidance for the rational application and management of MEM in neonatal sepsis patients. It should be noted that as the 12 recommendations are based on previous literature, the evidence level is not high and requires further clinical validation.

Conclusion

In view of the increasingly severe resistance situation in NICUs and the many issues in the clinical application of meropenem (MEM), we adopted standardized guideline development methods and processes, relied on the rich experience of authoritative experts, combined with the best evidence and patient preferences, and proposed 12 recommendations. These recommendations aim to optimize the clinical application of MEM, inspire more clinical research, and further improve the treatment efficacy and medication safety of neonatal intensive care units.

Professor Xiaomei Tong

Professor of Pediatrics, Peking University Third Hospital

18th National Committee Member and Secretary of the Neonatology Group, Chinese Pediatric Society, Chinese Medical Association

Standing Committee Member, Maternal and Child Nutrition Branch, Chinese Nutrition Society

Chairperson, Special Fund for Premature Infant Care, China Birth Defects Intervention Foundation

Chairperson, Premature Infant Committee, Neonatology Branch, Chinese Medical Doctor Association

Chairperson, Preterm and Preterm Infant Medicine Branch, Beijing Medical Association

Vice President, Neonatology Branch, Beijing Medical Doctor Association

Executive Director, Beijing Maternal and Child Health Association

Editorial Board Member, Chinese Journal of Pediatrics / Chinese Journal of Neonatology / Chinese Practical Pediatrics Clinical Journal / Chinese Contemporary Pediatrics Journal / Clinical Pediatrics Journal / International Pediatrics Journal / and other domestic core journal magazines

Main research directions: neonatal intensive care medicine, premature infant management, child development