Growing Threat of Macrolide-Resistant Mycoplasma pneumoniae Among Children: What We Know and What We Need.

Mycoplasma pneumoniae is a unique, wall-less bacterium and a leading cause of community-acquired pneumonia in school-aged children. Epidemiologically, M. pneumoniae causes endemic and epidemic infections every 3-5 years, with recent surges noted globally since mid-2023. Diagnostic challenges persist; although polymerase chain reaction and serology are widely used, both carry risks of false positives or negatives owing to prolonged shedding or delayed antibody responses, respectively. Novel approaches such as ELISpot assays for antibody-secreting cells may improve diagnostic accuracy. Macrolides remain the first-line treatment in children because of the toxicity of tetracyclines and fluoroquinolones. However, macrolide-resistant M. pneumoniae (MRMP) has emerged as a major concern, especially in the Western Pacific Region (South Korea, China, and Japan), where resistance rates have exceeded 80% in recent years. Resistance is developed by 23S rRNA mutations (notably A2063G) and driven primarily by macrolide over usage and clonal expansion-particularly in sequence type 3 strains. Despite high resistance rates, many M. pneumoniae pneumonia cases remain self-limiting, and clinical outcomes are not substantially different between macrolide-sensitive and macrolide-resistant infections. Clinical studies show that while MRMP is associated with longer fever and hospital stays, it rarely increases severity. Tetracyclines and quinolones have been shown to lead to faster fever resolution in MRMP patients, and treatment guidelines now recommend switching to second-line agents when macrolide-refractory disease is suspected. Nevertheless, a considerable proportion of patients recover spontaneously, regardless of antibiotic choice, likely owing to the self-limiting nature of the pathogen, misdiagnosis of viral infections, or the immunomodulatory effects of macrolides. Amid rising MRMP, this review highlights the complex interplay between bacterial resistance, diagnostic limitations, and host factors in shaping M. pneumoniae disease outcomes.