Severe Mycoplasma pneumoniae Pneumonia During the 2023–2024 European Re-Emergence: Why Severity Does Not Predict Macrolide Resistance

Background: Following a significant decline during the 2020–2021 SARS-CoV-2 pandemic, Mycoplasma pneumoniae (MP) experienced a resurgence across Europe in 2023–2024. Although macrolide-resistant MP has increased globally, severe disease can occur even in the absence of resistance, which highlights the importance of rapid molecular characterization for clinical purposes. In this context, clinical severity is often improperly used as a surrogate marker of macrolide resistance, potentially driving unnecessary antibiotic escalation. Methods: We report a severe MP pneumonia occurring during the 2023–2024 resurgence and evaluate macrolide resistance through a rapid two-step workflow (Real Time-PCR screening for A2063G/A2064G followed by confirmatory 23S rRNA sequencing), to assess whether severity predicts resistance and to support antibiotic stewardship. Results: The patient developed acute hypoxic respiratory failure (PaO2 54.9 mmHg; P/F ratio 110), extensive centrilobular micronodules on chest CT imaging, significant systemic inflammation and elevated liver enzymes. Respiratory support was escalated from a Venturi mask to a high-flow nasal cannula and BiPAP. MP infection was confirmed by multiplex Real Time-PCR (RT-PCR) and supported by positive IgM/IgG serology. RT-PCR targeting A2063G/A2064G mutations revealed no resistance-associated variants, and Sanger sequencing of an 807 bp 23S rRNA fragment confirmed a wild-type genotype. Despite severe hypoxemic respiratory failure, no resistance-associated variants were detected, documenting a clear severity–genotype mismatch. Clinical and radiological improvement followed second-line antibiotic therapy. Conclusions: Severe MP pneumonia can occur despite the absence of macrolide resistance. During MP re-emergence, clinical severity should not be used to infer macrolide resistance. Integrating nucleic acid amplification test (NAAT) diagnosis with rapid genotyping/confirmatory 23S rRNA sequencing can prevent misclassification, reduce unwarranted broad-spectrum escalation, and strengthen antimicrobial stewardship decisions.