Background: Mycoplasma pneumoniae is a major cause of respiratory tract infections. We aimed to investigate the spatiotemporal dynamics, antimicrobial resistance, and severity of the delayed re-emergence of infections with M pneumoniae after the implementation of non-pharmaceutical interventions (NPIs) against COVID-19.

Methods: Epidemiological data (positive and total test numbers, and macrolide-resistant M pneumoniae detections) and clinical data (hospitalisations, intensive care unit [ICU] admissions, and deaths) were collected through our global surveillance from April 1, 2017 to March 31, 2024. The moving epidemic method (MEM) was used to establish epidemic periods, and the time-series susceptible-infected-recovered (TSIR) model to investigate the delayed re-emergence.

Findings: The dataset included 65 sites in 29 countries from four UN regions: Europe, Asia, the Americas, and Oceania. A global re-emergence of M pneumoniae cases by PCR detection was noted from the second half of 2023. The mean global detection rate was 11·47% (SD 15·82) during the re-emergence (April, 2023-March, 2024). By use of MEM, the re-emergence was identified as epidemic in all four UN regions, simultaneously in ten countries at calendar week 40 (early October, 2023). Macrolide-resistant M pneumoniae rates from Europe and Asia were 2·02% and 71·22%, respectively, and did not differ between the re-emergence and pre-COVID-19 pandemic periods. During the re-emergence, some countries reported increased hospitalisations (in adults, two of ten countries; and in children, two of 14 countries) and ICU admissions (in adults, one of nine countries; and in children, two of 14 countries). Overall, 65 (0·11%) deaths were reported, without statistical difference between pre-COVID-19 pandemic and re-emergence. The TSIR model accurately predicted, considering a 3-week generation time of M pneumoniae and a 90% reduction in transmission through NPIs, the observed delayed re-emergence.

Interpretation: This large global dataset for M pneumoniae detections shows that although there was an unprecedented high number of detections across many countries in late 2023, the severity and number of deaths remained low. Our results suggest that the delayed re-emergence was related to the long incubation period of M pneumoniae infection.