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Doxycycline for Macrolide-Resistant Mycoplasma pneumoniae Pneumonia in Children: Clinical Updates and Therapeutic Insights Post-COVID-19
Received 6 January 2026
Accepted for publication 26 February 2026
Published 10 March 2026 Volume 2026:19 593954
DOI https://doi.org/10.2147/IDR.S593954
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Hazrat Bilal
Rongjie Chen,1,2 Zhe Xu1
1Department of Pediatrics, Guangyuan Central Hospital, Lizhou District, Guangyuan, Sichuan Province, 628000, People’s Republic of China; 2Department of Pediatrics, Guangyuan Central Hospital Affiliated to North Sichuan Medical College, Shunqing District, Nanchong City, Sichuan Province, 637000, People’s Republic of China
Correspondence: Zhe Xu, Department of Pediatrics, Guangyuan Central Hospital, Guangyuan, Sichuan, 628000, People’s Republic of China, Email [email protected]
Abstract: Mycoplasma pneumoniae (MP) is a leading cause of community-acquired pneumonia (CAP) in children. Macrolides have long been first-line therapy due to favorable safety profiles and low minimum inhibitory concentrations (MICs) in pediatric populations. However, the global surge in macrolide-resistant MP (MRMP) has compromised conventional treatments, creating an urgent need for alternative agents. Mounting evidence supports doxycycline, a second-generation tetracycline, as an effective therapy for pediatric MRMP, particularly post-COVID-19. Compared to azithromycin, doxycycline shortens disease duration, accelerates the resolution of fever and cough, promotes pulmonary infiltrate absorption, and yields robust outcomes in children ≥ 8 years old. It also reduces corticosteroid use and exhibits a favorable safety profile. For refractory MP pneumonia (RMPP), combination therapy with doxycycline and corticosteroids (eg, methylprednisolone) enhances therapeutic effects. Ongoing research explores innovative combinations and personalized dosing to mitigate resistance. This narrative overview synthesizes recent advances in doxycycline use for pediatric MRMP since the COVID-19 pandemic, aiming to inform evidence-based practice. It also highlights the need for large-scale, well-designed trials to confirm long-term safety and efficacy, supporting standardized clinical implementation.
Keywords: doxycycline, Pediatric mycoplasma pneumoniae pneumonia, macrolide resistance, clinical management, post-COVID-19
Introduction
Mycoplasma pneumoniae pneumonia (MPP) is a major cause of acute respiratory tract infections in children, particularly among those aged 2–12 years.1,2 As an atypical, cell wall-deficient intracellular pathogen, MP is inherently resistant to cell wall-targeting antibiotics (eg, β-lactams, glycopeptides).3 Macrolides have remained first-line therapy for decades, but rising MRMP prevalence—driven primarily by 23S rRNA gene mutations—has rendered them ineffective in many cases.4,5 Post-COVID-19, MP infections have rebounded sharply in Europe and Asia, with more severe clinical manifestations and higher pneumonia incidence in children.6,7 In China (Wuhan City, Hubei Province), the dominant P1-1 genotype of MP exhibits a macrolide resistance rate of up to 96% in 2020–2022,8 posing a critical threat to pediatric health. Doxycycline has emerged as a promising alternative, leveraging broad-spectrum activity, high bioavailability, and favorable safety profiles. This narrative overview synthesizes recent clinical evidence on doxycycline for pediatric MRMP, focusing on epidemiological trends, resistance mechanisms, therapeutic advantages, and clinical recommendations to guide frontline practice.9
Key terms used in this study are uniformly defined as follows:
MRMP (Macrolide-Resistant Mycoplasma pneumoniae): Defined by molecular mutation (23S rRNA gene A2063G/A2064G) and phenotypic MIC (minimum inhibitory concentration for erythromycin ≥16 μg/mL);10
Macrolide-refractory MPP: Clinical failure of macrolide monotherapy (azithromycin/clarithromycin) for 72 hours with persistent fever (>38.5°C) and no improvement in respiratory symptoms11(not identical to MRMP, as refractoriness may be due to inflammation rather than resistance);
RMPP (Refractory Mycoplasma pneumoniae Pneumonia): Defined by persistent fever >7 days despite appropriate antibiotic therapy, radiologic progression of pulmonary lesions, and elevated inflammatory markers (CRP >80 mg/L).11,12
Epidemiological Trends of Pediatric MP Infections Post-COVID-19 and the Macrolide Resistance Crisis
Pediatric MP infections exhibit distinct epidemiological patterns: seasonal peaks occur in winter (northern China) and summer-autumn (southern China), with a slight female predominance.13 During the COVID-19 pandemic, non-pharmacological interventions (eg, mask-wearing, social distancing) temporarily reduced MP transmission.14–16 However, relaxation of these measures triggered a marked resurgence in 2023–2025 (post-COVID-19 period, defined as the stage after the relaxation of global non-pharmacological interventions in late 2022), with MP becoming the leading pathogen of pediatric respiratory infections in China.16,17 The first rebound wave occurred in China and East Asia in 2023 Q2-Q4, and the second wave in Europe and Southeast Asia in 2024 Q1-Q3.18,19 This rebound is attributed to cyclical MP epidemiology, pre-existing high macrolide resistance, and potential post-pandemic immune dysregulation.20
Global MRMP prevalence varies substantially by region, with clear distinctions between resistance prevalence (chronic regional stable data) and outbreak reports (acute localized incidence increase).10 Europe reports localized MPP outbreaks (eg, Italy, Scotland, Czech Republic) with a resistance prevalence of 20–30%,21–23 while Asia bears the highest burden—central China has a resistance rate of 90–96%,10,24 followed by Japan with 60–70%.25 Such global heterogeneity is associated with differences in antibiotic use patterns, diagnostic ascertainment (molecular vs. culture-based testing), and regional epidemiological characteristics.24 Culture-based testing may underestimate resistance rates due to the fastidious growth of Mycoplasma pneumoniae, while molecular testing (PCR for 23S rRNA mutations) is more sensitive but less widely available in low-resource regions.26–28
Resistance is primarily mediated by point mutations in the V domain of the 23S rRNA gene (A2063G or A2064G),29,30 which reduce macrolide binding to ribosomal targets. A study on influenza-like illness cases in China found that among Mycoplasma pneumoniae positive samples in children, the mutation rate of A2063G was 48.00%, A2064G was 8.00%, and 8.00% were double mutations of both A2063G and A2064G.31
Epidemiological data from Ningbo, China, during the 2022–2023 season showed that the mutation rate of A2063G/A2064G exceeded 70%, reaching 100% in some months.32 A systematic review and meta-analysis showed that in Asia, the prevalence of the A2063G mutation ranges from approximately 91% to 100%, while the prevalence of the A2064G mutation ranges from approximately 2% to 100%.33 This widespread resistance has necessitated a shift to alternative antibiotic classes, including tetracyclines and fluoroquinolones.29
Pathophysiology of MP and RMPP
MP’s lack of a cell wall enhances environmental adaptability and immune evasion.34,35 Pathogenesis involves high-affinity adhesion to respiratory epithelial cells via membrane proteins, leading to direct cellular injury and a robust inflammatory cascade driven by proinflammatory cytokine release.36 Most MP infections present as self-limiting upper respiratory tract disease, but a subset of children progresses to RMPP—characterized by dysregulated inflammation, extensive airway damage (eg, bronchial mucosal necrosis), and pulmonary consolidation.37,38 MP may also induce extrapulmonary complications (eg, cutaneous rashes, neurological sequelae) via molecular mimicry or immune complex deposition.37,39 Recent transcriptomic studies have identified distinct circular RNA (circRNA) profiles in RMPP versus non-refractory MPP, implicating circRNAs in regulating inflammatory pathways and offering potential diagnostic biomarkers and therapeutic targets.40
Mechanisms of Macrolide Resistance in MP
Macrolide resistance in MP is multifactorial, with point mutations in the 23S rRNA gene as the primary driver.29,41 The A2063G mutation is the most prevalent, followed by A2064G, both reducing macrolide-ribosome binding affinity and diminishing antimicrobial efficacy.42 Secondary mechanisms include plasmid-mediated horizontal transfer of resistance determinants, target gene mutations altering protein structure/function, and adaptive strategies (eg, cell membrane modifications, biofilm formation) that enhance MP’s ability to withstand antibiotic pressure.43–45 These mechanisms collectively contribute to the global spread of MRMP and highlight the need for antibiotics with distinct modes of action, such as doxycycline.46,47
Therapeutic Advantages and Safety of Doxycycline for Pediatric MRMP
Doxycycline vs. Conventional Alternatives
Fluoroquinolones and tetracyclines are the main alternatives for MRMP, but fluoroquinolones are contraindicated in children due to musculoskeletal risks (eg, joint pain, tendon disorders).47,48 Doxycycline demonstrates a more acceptable safety profile in clinical application: adverse effects are mild and transient, primarily gastrointestinal disturbances (eg, nausea, diarrhea), esophagitis, and photosensitivity.49,50 Unlike earlier tetracyclines, doxycycline has a lower calcium-binding affinity, which may reduce the risk of tooth discoloration in children during tooth development with short-term use (≤21 days);49,50 however, potential tooth discoloration remains a minor concern in clinical practice, and rigorous risk-benefit assessment is still recommended for children <8 years old.49,50 The American Academy of Pediatrics (AAP) Red Book removed the warning on doxycycline-induced tooth discoloration in 2018, endorsing its short-term use in children of all ages when clinically indicated.51
Clinical Efficacy
Clinical studies and meta-analyses confirm doxycycline’s efficacy in pediatric MRMP.52 In children ≥8 years old with mild-to-moderate MRMP, compared to azithromycin, it can shorten the time to fever resolution by approximately 2–3 days, reduce the time to cough resolution by approximately 3–5 days, accelerate the absorption of pulmonary lesions, and lower levels of inflammatory markers (such as C-reactive protein).53,54 A retrospective study of pediatric lobar pneumonia caused by MRMP found doxycycline reduced hospitalization length by 30% compared to extended-release azithromycin.53,54 Meta-analyses further confirm that doxycycline yields better clinical cure rates and symptom resolution outcomes than macrolide-based regimens in pediatric MRMP patients.52 In refractory MRMP (RMPP), doxycycline combined with methylprednisolone can reduce hospitalization time by approximately 30%, which is superior to monotherapy with macrolides.52–54
Combination Therapy
For RMPP, doxycycline combined with methylprednisolone modulates excessive inflammation and improves outcomes.55–58 Other synergistic combinations include doxycycline plus compound furazolidone (reducing inflammation and hospitalization duration) and doxycycline plus hydroxychloroquine (showing better safety and clinical effects than hydroxychloroquine-azithromycin combinations during COVID-19).59,60 Bronchoalveolar lavage combined with doxycycline also enhances clinical response rates in severe MRMP cases.50,57,58
Innovative Perspectives on Resistance Management
Doxycycline addresses antimicrobial resistance through three key mechanisms, with its immunomodulatory effects supported by in vitro and clinical evidence:
Dual therapeutic action: It inhibits bacterial protein synthesis and exerts immunomodulatory effects by inhibiting the release of proinflammatory cytokines (eg, IL-6, TNF-α) and reducing neutrophil infiltration in the lung tissue,61,62 which differentiates it from macrolides and contributes to its efficacy in severe MRMP with excessive inflammation. Recent real-world studies on children with MRMP pneumonia support the efficacy of doxycycline. These studies indicate that doxycycline remains highly sensitive to macrolide-resistant strains, making it an effective alternative treatment option, with its effects possibly partly attributed to antibacterial and potential immunomodulatory effects.50,53 By inhibiting bacterial metalloproteases, it also disrupts resistance mechanisms in severe infections (eg, ventilator-associated pneumonia).59
Novel therapeutic strategies: Synergistic combinations (eg, doxycycline + polymyxin B)63 and advanced delivery systems (eg, microfluidic lipid-based nanocarriers)64 enhance bioavailability and reduce systemic adverse effects, further improving the clinical application value of doxycycline.
Personalized medicine integration: Genotype profiling and antimicrobial susceptibility testing guide tailored dosing, duration, and combinations, mitigating resistance at the individual level.50,53
Clinical Recommendations and Future Directions
Clinical Practice Guidelines
Indications: Doxycycline is recommended as a first-line alternative for MRMP in children ≥8 years, particularly in macrolide-refractory cases or with confirmed 23S rRNA mutations.54,65 For children <8 years, it may be considered in severe MRMP (eg, RMPP, respiratory failure) after rigorous risk-benefit assessment.65
Administration: Short-term courses (≤21 days) are preferred to minimize adverse effects. Oral doxycycline has high bioavailability and pulmonary tissue penetration, suitable for both outpatient and inpatient use.54
Safety monitoring: Patients should avoid direct sunlight (to prevent photosensitivity) and take the drug with food (to reduce gastrointestinal irritation).10,53 Routine laboratory monitoring is unnecessary for courses ≤21 days.53
Antimicrobial stewardship: Doxycycline use should be guided by susceptibility testing or molecular diagnostics to reduce unnecessary exposure and delay resistance.50
Future Research Priorities
Systematic evaluation of doxycycline’s safety and efficacy in children <8 years, including long-term effects on growth and development.51,66 Development of precision treatment protocols integrating genotypic analysis (eg, 23S rRNA mutation status) to optimize dosing and combinations.50,66,67 Investigation of innovative formulations (eg, nanocarriers) to enhance bioavailability, stability, and tissue targeting.68 Large-scale, multicenter prospective trials involving multi-ethnic populations to confirm comprehensive efficacy in complex infections (eg, RMPP).69
Methodological Considerations and Limitations
This narrative overview synthesizes peer-reviewed clinical studies, meta-analyses, and clinical guidelines on doxycycline for pediatric MRMP published between 2019 and 2025, retrieved from PubMed, CNKI, and Web of Science. Unlike systematic reviews, this study does not include a standardized search strategy, inclusion/exclusion criteria, study selection process, risk of bias assessment, or PRISMA flow diagram, which is a typical characteristic of narrative overviews.
This review is limited by the lack of a systematic search strategy and risk of bias assessment; the evidence is dominated by retrospective studies, and large-scale prospective trials in children <8 years old are lacking. In addition, the included clinical data are mainly from Asian and European regions, and the applicability of the conclusions to other regions needs to be further verified.
Conclusion
Doxycycline is increasingly recognized as a viable and generally safe treatment option for pediatric macrolide-resistant Mycoplasma pneumoniae pneumonia, particularly in the wake of the COVID-19 pandemic.70 Its dual mechanisms—bacterial protein synthesis inhibition and anti-inflammatory activity—enable effective control of MRMP and modulation of excessive inflammation in severe cases.71 Compared to fluoroquinolones, it exhibits a more favorable safety profile in short-term use, with mild, transient adverse effects and a reduced risk of tooth discoloration in pediatric patients.10,72,73 Combination therapy with corticosteroids or other agents further enhances clinical efficacy in refractory cases.10 Clinical practice should prioritize antimicrobial stewardship, with doxycycline use guided by susceptibility testing or molecular diagnostics.50,53 Future research focusing on younger children, precision medicine, and novel formulations will strengthen the evidence base, addressing the global challenge of antimicrobial resistance and improving pediatric respiratory health outcomes. At the same time, multi-center, cross-regional prospective studies are needed to further verify the long-term safety and clinical efficacy of doxycycline in pediatric MRMP treatment.
Data Sharing Statement
This review is based on previously published clinical and epidemiological data.
Acknowledgments
The authors thank Guangyuan Central Hospital for providing clinical data, North Sichuan Medical College for academic support, and Professor Zhe Xu for guidance on research design and manuscript revision.
Disclosure
The authors declare no potential conflicts of interest in this work.
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