Community-acquired pneumonia (CAP) is most prevalent among children under 5 years old (1). Identifying CAP typically involves a thorough assessment of the patient's medical history, clinical symptoms, physical examination, laboratory tests, and imaging results (2). In children under 5 years old, the most commonly identified bacteria causing CAP include streptococcus pneumoniae, streptococcus pyogenes, klebsiella pneumoniae, escherichia coli, staphylococcus aureus (SA), haemophilus influenzae, haemophilus parainfluenzae, and moraxella catarrhalis (3, 4). The presence of significant pleural effusion or extensive multi-lobar infiltrates or consolidations on lung imaging is often indicative of necessity of hospitalization, disease severity, need for intensive care unit (ICU)-level care and organ function support, and a less favorable prognosis (5, 6). Prompt diagnosis, pathogen identification, risk stratification, and subsequent targeted antimicrobial therapy are vital for favorable outcomes in children with CAP (7). In clinical practice, initial choices of antimicrobial therapy for most cases of CAP in children under 5 years of age are typically based on local epidemiology, risk factors assessment, and subsequent clinical parameters and culture results, which can lead to the underdiagnosis and underestimation of lung infections caused by uncommon pathogens (8). By amplifying and sequencing the nucleic acids of isolated pathogens, metagenomic next-generation sequencing (mNGS) can offer superior performance in identifying pathogens from various body parts with higher sensitivity and diagnostic specificity than traditional pathogen detection methods, particularly for rare pathogens (9, 10).

Although not the most common, staphylococcus aureus (SA), including the methicillin-resistant SA (MRSA) variant, does play a role as one of the pathogens responsible for pediatric CAP, which can be partly attributed to its natural colonization in the airways (11, 12). More importantly, SA-induced CAP is associated with unfavorable clinical outcomes compared to the common pneumococcal CAP, involving a higher risk for sepsis and septic shock, need for ICU-level care and organ function support, and significant mortality, regardless of the presence of methicillin-resistance (13, 14). However, the current practice of empirical antimicrobial agents for MRSA-induced lung infections remains suboptimal in consideration of potential adverse drug reactions (ADRs) associated with first-line anti-MRSA antimicrobial agents, leading clinicians have to carefully weigh the pros and cons of antibiotic choices (15, 16). This predicament underscores the pressing need for the development of new antibiotics, leading to the emergence of contezolid. Conteziold, an orally administered oxazolidinone antibiotic, gained approval from the National Medical Products Administration (NMPA) of China in June 2021 for managing complicated skin and soft tissue infections (cSSTI) caused by SA, streptococcus pyogenes, or streptococcus agalactis (17). Owing to its enhanced safety profile and ongoing clinical progress, the scope of contezolid's clinical application continues to expand, benefiting a growing number of patients with Gram-positive bacterial infections (18–21).

Notably, there have been no reports of the clinical application of contezolid in treating severe CAP caused by SA in the toddler. In this report, we present, for the first time, the compassionate use of contezolid in the treatment of severe CAP induced by SA in a toddler, demonstrating its favorable therapeutic efficacy and enhanced safety profile.

CAP, usually considered as a major global health issue, represents a leading cause of hospitalization, large consumption of antibiotics, need for ICU-level care and organ function support, and substantial mortality in pediatric population younger than 5 years, thus posing a significant threat to childhood health, placing a huge burden on healthcare systems, and presenting a grand challenge to clinical management (7, 22, 23). As a common acute lower respiratory tract infection, pediatric CAP is characterized by a predominance of respiratory viruses over other pathogens, with RSV being the most frequently isolate, especially in pediatric population under 2 years of age (24, 25). However, the etiologies and prevalences of CAP vary substantially depending on the age breakdowns, individual susceptibilities, clinical settings, geographical regions, seasons and epidemiological characteristics (26, 27). For instance, in Saudi Arabia, SA, a Gram-positive bacterium, has been identified as one of the major contributors to pediatric CAP (28). Additionally, SA is a frequent pathogen of bloodstream infection (BSI), which can worsen the condition in children with CAP (29, 30). Finally, local or systemic complications, acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), multiple organ involvement or even dysfunction often serve as crucial clinical indicators of disease deterioration and poor prognosis in children with CAP, and SA is one of the common culprits (31).

SA can be categorized into methicillin-susceptible SA (MSSA) and MRSA based on the presence or absence of methicillin-resistance, with panton-valentine leukocidin (PVL) being one of the most important virulence factors to cause leukocyte lysis and tissue necrosis in clinical settings (12, 32). Consequently, SA is an extreme-virulent and high-pathogenic Gram-positive bacterium and capable of rapidly developing antibiotic resistance (33). Furthermore, the prevalences of SA-induced a series of diseases have shown a steadily increasing trend over the years due to the introduction of pneumococcal conjugate vaccines (PCVs) (34, 35). Prompt and accurate pathogen identification provides objective scientific evidences for optimal amtimicrobial stewardship strategies to reduce excessive use of antibiotics, secondary resistance of strains, potential ADRs and unnecessary costs. However, challenges such as insufficient awareness of pathogen detection, limited access to pathogen acquisition, low positive yield and relative hysteresis of traditional detection methods, and uncertainty of detection results significantly impede the timely and precise management of CAP in clinical practice (36). Rapid, highly accurate, readily available, and cost-effective microbiological diagnosis for the etiologies of CAP may be a breakthrough for this predicament. With its extensive clinical application, mNGS has gradually demonstrated greater potential than traditional detection methods for early pathogen identification to facilitate rational use of antibiotics, especially in BALF samples from patients undergoing IMV (37–39).

In this toddler, mNGS of BALF sample collected immediately after IMV revealed the culprit was SA with natural resistance to aztreonam, polymyxin B/colistin and nalidixic acid. Despite the lack of detection of methicillin-resistance, first-line anti-MRSA antimicrobial agents were chosen for salvage therapy in view of disease severity, progress in lung imagings, and multi-organ involvement of the toddler upon admission. Even if the responsible pathogens are identified, antibiotic regimens must take into account some specific clinical characteristics such as pharmacokinetics (PK), pharmacodynamics (PD) and potential ADRs associated with the selected antibiotics, disease severity, immune status, organ function and economic affordability of patients, and history of antibiotic use (40). More importantly, failure in initial empirical antimicrobial therapy can be associated with unfavorable outocmes (41). The decision to off-label use of contezolid was driven by concern about potential ADRs associated with vancomycin and linezolid, which could further make the already serious condition worse (18). Although contezolid is officially approved for managing cSSTI induced by SA, streptococcus pyogenes or streptococcus agalactis, but in fact, it has demonstrated broad-spectrum and potent activity against Gram-positive bacteria from various parts of the body, including multidrug-resistant (MDR) strains, in both in-vivo and in-vitro studies with an improved safety and tolerability profile through minimizing effects associated with myelosuppression and monoamine oxidase (MAO) inhibition (18, 19, 42–45). As the only completely synthetic class of antibiotic, contezolid exerts a unique mechanism of action by inhibiting targeted protein synthesis and exhibits excellent dissemination to lung tissues (46). After continuous oral administration of contezolid (200 mg twice daily) for 15 days on ordinary fed status, the toddler achieved the expected therapeutic effect and favorable outcome without any ADRs. In addition, high CSF permeability of unbound contezolid has been demonstrated in a patient with tuberculous meningoencephalitis, suggesting the therapeutic potential of contezolid for CNS infections (47).

Another noteworthy issue in this case was the occurrence of secondary multiple ICH and ischemic changes in the white matter behind the bilateral lateral ventricles following severe CAP, which was really a rare phenomenon in clinical practice. These near-complete negative CSF tests dispelled our initial suspicions of a CNS infection. During the subsequent multidisciplinary team (MDT) discussion, the majority consensus was that these neurological abnormalities were primarily linked to severe CAP-induced MODS, especially coagulation dysfunction. Insufficient evidence existed to suggest the involvement of secondary cytokine storm in the brain. An open question for consideration was whether 12-day systemic antibiotic therapy in conjunction with 5-day Ig pulse could eliminate the pathogens responsible for these neurological abnormalities, even though we were not inclined to favor this possibility. The last follow-up lung CT scan on the 126th day after discharge indicated bronchitis with localized inflammation, suggesting that it might take longer to repair SA-caused severe lung damage in the toddler. The results of the last brain MRI scan and neurological follow-up revealed the persistent severity of brain injury and sequelae in the toddler with SA-induced severe CAP, which could have a substantial impact on the growth and development of children.

A limitiation of this study is the lack of objective conditions for monitoring PK and PD of contezolid, which is particularly important when using newly developed drugs in pediatric patients, especially for off-label use. In addition, the successful application of contezolid in the management of SA-induced severe CAP in this toddler is only a case report, which is not universal, and can not be directly extended to similar patient populations or indications. Lastly, although this toddler was followed up to 280 days after discharge, it was still insufficient.

Although contezolid has not been officially indicated for CAP, it has been shown to be effective and safe in the management of SA-induced severe CAP in this toddler, suggesting its potential as an alternative option in the dilemma, especially for patients who are susceptible or intolerant to ADRs associated with first-line anti-MRSA antimicrobial agents. Future efforts should concentrate on confirming our findings through more similar cases and well-designed clinical trials.