Globally, sepsis remains the leading cause of death among infants and children, with an estimated 1.6 million pediatric deaths annually. Although our understanding of the pathophysiology of sepsis has deepened over the past two decades, advances in research have not been translated into clinical practice with sufficient efficacy. Currently, treatment of sepsis continues to rely primarily on antimicrobial therapy and comprehensive supportive care, and timely, appropriate antibiotic administration is closely linked to patient outcomes.

　　 1. The Role of Antibiotics in the Treatment of Sepsis

　　Sepsis is, in essence, the body’s response to an invasion by foreign pathogens; without infection, sepsis cannot occur. Conversely, in the absence of a host response to pathogen invasion, sepsis likewise does not develop. Following microbial entry into the host, innate immune mechanisms are activated, triggering defensive responses across multiple systems and organs, which may clinically manifest as a systemic inflammatory response.

　　The activation of these systems and the intricate “networked communication” among them play a crucial role in preventing the spread of infection and eliminating pathogens. On the other hand, excessive and sustained inflammatory responses are a major contributor to tissue damage, which explains why, despite the ability of antibiotics to eradicate bacteria, some pediatric patients still succumb to death. The depletion of cytokines and inflammatory mediators resulting from an overactive inflammatory response can also plunge the host into an immunosuppressed state, further increasing susceptibility to diverse infections and serving as a significant factor underlying recurrent infections and even mortality.

　　Persistent pathogenic microorganisms and sustained host responses are the primary drivers of septic shock, multiple organ dysfunction, and even death in pediatric patients with sepsis. Therefore, it is inappropriate to overemphasize the detrimental effects of excessive host responses while neglecting the role of pathogens. In recent years, numerous therapies targeting host responses—such as anti‑inflammatory or anticoagulant strategies—have largely failed, underscoring that the pathogenic contribution of microorganisms must not be overlooked in favor of an exclusive focus on exaggerated host reactions. Consequently, given our current understanding and research capabilities, comprehensive treatment guided by evidence‑based medicine is essential to reduce mortality to some extent.

　　Any attempt to identify a universal “magic bullet” remains unrealistic at present. In the context of comprehensive treatment, timely and appropriate antimicrobial therapy and prompt debridement of infection foci are of paramount importance and form the cornerstone of sepsis management. Epidemiological studies indicate that the vast majority of cases of sepsis are attributable to bacterial infections; therefore, early, judicious use of antibiotics is a critical component in reducing mortality. Proper antibiotic administration can prevent more than 50% of pediatric sepsis cases from progressing to severe sepsis, thereby lowering the mortality rate by 10% to 15%.

　　A wealth of evidence indicates that early, appropriate use of antibiotics can significantly reduce mortality; for severe sepsis, each hour of delay in initiating adequate antibiotic therapy is associated with a 7.6% increase in mortality. Although the role of antibiotics becomes limited in the later stages of severe sepsis, controlling the infection remains the cornerstone of successful resuscitation—without effective infection control, even the most sophisticated organ‑support measures will be futile. During antibiotic therapy, it is essential to seize the optimal therapeutic window, select broad‑spectrum agents that cover the likely pathogens, and ensure an adequate duration of treatment. Appropriate antibiotic management not only markedly lowers mortality but also shortens hospital stays and reduces healthcare costs. Consequently, eradication of the pathogen represents a critical component of future sepsis‑management strategies.

　　 2. Rational Use of Antibiotics in the Treatment of Sepsis

　　In addition to the timely administration of antibiotics being closely linked to prognosis, the use of the appropriate antibiotic—i.e., one that can effectively eradicate the pathogen, as confirmed by susceptibility testing, or, in cases of negative cultures, adherence to guideline-recommended therapy for a specific pathogen in a given setting—should be another critical factor influencing outcomes. In one study, mortality was significantly higher among patients receiving inappropriate antibiotic therapy (61.9%), substantially exceeding that of the control group receiving appropriate treatment (28.4%).

　　In another retrospective case series of 5,175 patients with septic shock, mortality was five times higher among those who received inappropriate antibiotic therapy compared with the control group. Thus, the use of an ineffective antibiotic in the initial treatment markedly increases mortality. Antibiotic selection is typically divided into empirical therapy—when the pathogen is unknown—and targeted therapy—when the pathogen is identified. In clinical practice, the vast majority of initial antibiotic regimens are empirical; however, this “empirical” approach does not rely on individual experience but rather on a comprehensive assessment grounded in epidemiology, evidence-based medicine, and the patient’s specific clinical context. Moreover, the initiation of antibiotic therapy must take multiple factors into account.

　　2.1 Epidemiological Data Pathogen testing and the selection of appropriate antibiotics are critical to the rational use of antimicrobial agents. Epidemiological data are essential; it is important to identify the common pathogens responsible for a given disease in a specific country, region, or even hospital, and to assess bacterial susceptibility and resistance patterns to antibiotics. Following the diagnosis of sepsis, it is imperative to localize the source of infection—whether pulmonary, central nervous system–related, hematogenous, or urinary—and to determine whether any occult foci of infection are present.

　　Determining the site of infection helps to identify the causative pathogen: urinary tract infections and intra-abdominal infections are predominantly caused by Gram-negative bacteria; pulmonary infections are mainly due to Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis; skin and soft-tissue infections are typically associated with cocci such as Staphylococcus aureus and streptococci; and intracranial infections are commonly caused by Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, and other pathogens.

　　Clearly distinguishing between nosocomial and community‑acquired infections is also an important factor in identifying the causative pathogen. For example, the common pathogens of community‑acquired pneumonia and hospital‑acquired pneumonia differ, as do their patterns of antimicrobial resistance; consequently, treatment decisions vary accordingly. The patient’s age is another critical consideration in pathogen analysis, since the spectrum of pathogens can differ across age groups. Take pediatric community‑acquired pneumonia as an example: in infants and young children, viruses are typically the predominant etiologic agents, with Streptococcus pneumoniae and Haemophilus influenzae being the main bacterial causes, whereas in older children, Mycoplasma pneumoniae and Chlamydia pneumoniae predominate, with Streptococcus pneumoniae remaining the principal bacterium. In the neonatal period, β‑hemolytic streptococci and Escherichia coli are among the most frequent pathogens. Therefore, initial empirical therapy is guided by epidemiological data to select appropriate antibiotics.

　　2.2 Assessment of Disease Severity Accurate assessment of disease severity is critical for determining empirical treatment strategies and selecting appropriate antibiotics.

　　For uncomplicated infections, relatively narrow-spectrum first-line agents may be used; in cases of severe sepsis and septic shock, a “heavy‑hitting” approach is warranted, requiring broad‑spectrum coverage and combination antibiotic therapy, with due consideration of antimicrobial resistance. Once the patient’s condition has stabilized, targeted treatment should be initiated based on the results of pathogen‑specific testing. For example, in a patient presenting with septic shock, we typically administer carbapenems in combination with vancomycin—providing broad coverage while addressing potential bacterial resistance—in order to rapidly control bacterial proliferation, reduce the pathogen load, and thereby mitigate the host response and tissue damage.

　　However, we also oppose the indiscriminate use of second- and third-line broad-spectrum antibiotics regardless of disease severity. In fact, the overuse of such agents is a serious problem, leading to the emergence of resistant pathogens and even superbugs, which warrants urgent attention. For example, it is inappropriate to initiate piperacillin–tazobactam combined with vancomycin in a patient with empyema who presents without signs of shock or other severe sepsis manifestations. Furthermore, once the causative pathogen is identified, targeted therapy or de-escalation should be implemented. Specific drug choices are listed in Table 1.

　　2.3 Host Immune Status When the host is immunocompromised—such as in patients with immunodeficiency, diabetes, or renal disease; those receiving long-term immunosuppressive therapy, including corticosteroids; chemotherapy patients; organ transplant recipients; or cancer patients—opportunistic infections are common and tend to progress rapidly. In such cases, infections are often difficult to control, necessitating a treatment approach that differs from that used in immunocompetent individuals. This typically involves broad-spectrum, aggressive regimens and combination therapy.

　　2.4 Monotherapy and Combination Therapy

　　In principle, it is preferable to address the problem with monotherapy. Clinically, combination therapy is primarily employed to harness synergistic effects and to cover a broader spectrum of pathogens, thereby enhancing the success rate of empirical treatment.

　　For example, the combination of β‑lactam and aminoglycoside antibiotics exhibits synergistic effects. However, in pediatrics, due to limitations imposed by adverse drug reactions, aminoglycosides and quinolones are often restricted, leaving few therapeutic options. Consequently, combination therapy in pediatric practice is primarily aimed at covering diverse pathogens. For instance, given the high incidence of co‑infection with Streptococcus pneumoniae and Mycoplasma pneumoniae in older children, β‑lactams are frequently combined with macrolide antibiotics, a strategy that has been supported by evidence‑based medicine. In severe infections, β‑lactams are often used in combination with vancomycin or antifungal agents to ensure coverage of multiple pathogens. Similarly, combination regimens are employed when treating certain multidrug‑resistant organisms, such as Pseudomonas aeruginosa and Acinetobacter species.

　　2.5 Drug Dosage and Administration Intervals Based on their pharmacodynamic and pharmacokinetic profiles, antibiotics can be classified as concentration‑dependent or time‑dependent; for example, most penicillins and cephalosporins are time‑dependent. 2.8 Adverse Reactions Due to the unique characteristics of pediatric patients, drug selection must take potential adverse reactions into account. For instance, chloramphenicol may cause gray baby syndrome and bone marrow suppression; therefore, its use should generally be avoided. Aminoglycoside antibiotics are prone to ototoxicity and nephrotoxicity, so they should be used with caution in young children. In principle, if hepatic or renal impairment is already present, drugs that could exacerbate such damage should be avoided whenever possible.

　　2.9 Emphasizing the impact of prior antibiotic therapy on antibiotic resistance in hospitalized pediatric patients. When selecting antibiotics, a patient’s antibiotic treatment history is an important reference. Whether administering empirical or targeted therapy, attention must be paid to bacterial resistance, which has become a critical factor determining the success or failure of sepsis management. Pseudomonas aeruginosa, Staphylococcus aureus, and Acinetobacter species are often associated with high rates of resistance and are among the pathogens most likely to result in treatment failure; in such cases, combination antibiotic regimens may be necessary to improve cure rates.

　　The rate of resistance among Streptococcus pneumoniae is also on the rise and warrants close attention. For instance, in China, macrolide resistance in this pathogen approaches 100%, and monotherapy with macrolides for S. pneumoniae infections carries a very high risk of treatment failure, particularly in infants and young children under two years of age. It should be noted, however, that more expensive agents with broader antimicrobial spectra are not necessarily appropriate for all infections; for example, carbapenems are widely regarded as “effective” drugs, but they may not be the optimal choice when treating community‑acquired pneumonia caused by S. pneumoniae.

　　2. 10 Targeted therapy is the optimal approach; the most effective antibiotic treatment should be guided by a clear identification of the pathogen. Therefore, before initiating empirical antibiotic therapy, timely microbiological cultures should be performed to identify the source of infection and the causative agent. This is crucial for selecting appropriate targeted agents and for guiding drug choices after empirical therapy, and it is closely linked to the success of treatment. Even when initial therapy is empirical, the search for a definitive pathogen should not be abandoned throughout the course of management. Furthermore, in a substantial proportion of pediatric patients with sepsis, no etiological evidence is identified; nevertheless, if clinical suspicion of bacterial infection remains high, antibiotic therapy should still be administered.

　　In summary, the use of antibiotics remains the most critical therapeutic intervention in the management of sepsis, and appropriate antibiotic therapy can significantly reduce mortality in pediatric patients with sepsis.

　　2.11 Pay attention to the accuracy of the diagnosis. When antibiotic therapy proves ineffective, consider revisiting the diagnostic workup—such as whether a bacterial infection is present, whether it involves a specific pathogen (e.g., Mycobacterium tuberculosis, Brucella, or fungi), and also assess for any underlying foci of infection.

　　 3 Other Strategies for Anti-Infective Therapy in Sepsis

　　Antimicrobial therapy for sepsis is a comprehensive endeavor that must account for the interactions among the host, pathogenic microorganisms, and antibiotics. Among these factors, debridement of the infection site plays a critical role in controlling the infection; otherwise, relying solely on antibiotics often fails to achieve the desired outcome. For pediatric patients with surgical infections such as appendicitis, peritonitis, or empyema, early surgical intervention is essential. In cases of empyema, antibiotic therapy alone frequently falls short of the expected therapeutic efficacy—even when so‑called “high‑end” antibiotics are employed—whereas children who undergo chest tube drainage and receive standard antibiotics typically recover rapidly.

　　Furthermore, enhancing the body’s immune defenses remains the most fundamental measure for preventing infection; individuals with compromised immunity should receive immunomodulatory therapy to ensure that antibiotics can exert their full therapeutic effect. Given that sepsis is associated with immune suppression, interleukin‑7 has been used to stimulate lymphocyte proliferation and promote their recruitment to sites of infection; this agent has already undergone clinical trials in patients with HIV/AIDS, hepatitis C, and hepatocellular carcinoma to bolster immune function. PD‑1 is a receptor expressed on the surface of lymphocytes that can inhibit T‑cell proliferation,

　　It produces cytokines and exerts cytotoxic effects; during sepsis, PD‑L expression is upregulated, and administration of a PD‑1 antagonist can improve animal survival, suggesting that it may serve as a future target for immunotherapy. Furthermore, blood purification can simultaneously remove both pro‑inflammatory and anti‑inflammatory mediators, making it an important strategy for immune modulation in the future.

　　Author: Liu Chunfeng Source: Chinese Journal of Pediatric Emergency Medicine