Analysis of Clinical Characteristics and Risk Factors of Pediatric Macrolide-Resistant Mycoplasma pneumoniae Pneumonia from 2023 to 2025: A Single-Center Retrospective Study

Abstract

Introduction

Since 2023, re-emerging Mycoplasma pneumoniae (MP) with high macrolide resistance has challenged pediatric care.

Methods

We retrospectively analyzed 310 children hospitalized with MP pneumonia (MPP) from 2023 to 2025.

Results

Compared with macrolide-susceptible MPP (MSMPP) patients, those with macrolide-resistant MPP (MRMPP) had significantly shorter fever duration (median 5 vs 7 days) and hospital stay (median 9 vs 11 days), but more frequently received alternative antibiotics and glucocorticoids. The macrolide resistance gene positivity rate peaked at 97.3% in 2024. MRMPP patients showed elevated white blood cell counts, more pulmonary consolidation, and higher rates of tracheal occlusion. However, resistance genes were not significantly linked to severe MPP. Independent risk factors for MRMPP included albumin, pulmonary consolidation, and tracheal occlusion.

Discussion

The role of resistant MP in severe disease remains controversial, clinicians should not interpret resistance mutations in isolation but tailor therapy based on clinical and radiological findings to prevent progression.

Introduction

Mycoplasma pneumoniae (MP) is a leading cause of pediatric community-acquired pneumonia (CAP), responsible for 10%–40% of cases and representing a major contributor to both CAP incidence and associated mortality in children.^1,2 While MP infections are often self-limiting, typically presenting with mild symptoms and a favorable prognosis, besides pulmonary manifestations, MP can cause extrapulmonary complications including skin rashes, myocarditis, encephalitis, and hemolytic anemia, which add to the disease burden.³ The pathogen exhibits epidemic cycles every 3–7 years, each lasting 1–2 years. Notably, since 2023, a significant surge in pediatric MP infections has been observed worldwide. In China, for instance, the reported infection rate reached 47.89% in 2023.⁴ As an atypical bacterium lacking a cell wall, MP is inherently resistant to β-lactam antibiotics. Consequently, macrolides have been established as the first-line therapy for its infection. However, alongside the rising global incidence of MP in children and the extensive use of macrolides, the prevalence of macrolide-resistant strains has increased significantly, with reported rates now exceeding 90% in some regions.^5,6 Without timely intervention, MP pneumonia (MPP) can progress to severe disease, and together with its rare but serious complication of pulmonary embolism, it poses a great threat to children’s lives and health. Therefore, the rapid and accurate identification of the pathogen and the prompt initiation of appropriate antibiotic therapy are critical for reducing mortality and improving patient prognosis.

This study retrospectively analyzed data from 310 pediatric patients with MPP who underwent testing for macrolide resistance genes. We aimed to delineate the clinical characteristics of MPP in the post-pandemic era and to identify risk factors for macrolide-resistant MPP (MRMPP). Our findings are intended to provide clinicians with diagnostic insights for the early identification of drug-resistant cases, thereby enabling timely intervention, improving treatment outcomes, and reducing the risk of complications and serious sequelae.

Materials and Methods

Data Sources

This retrospective study was conducted at Chengdu Women’s and Children’s Central Hospital, a tertiary referral children’s hospital. We analyzed demographic information, clinical symptoms, and laboratory data-including complete blood count, liver and kidney function, coagulation profile, respiratory pathogen testing, and chest imaging-from children hospitalized with MPP at Chengdu Women and Children’s Central Hospital between February 2023 and May 2025. All included patients underwent testing for macrolide resistance genes. A total of 310 samples were collected and sent to Chengdu Huayin Medical Laboratory for detection of macrolide resistance genes (A2063G/A2064G). Patients were categorized by time of admission, age, gender, presence of macrolide resistance genes, and disease severity. SMPP was defined by the presence of persistent high fever, neurological symptoms, respiratory distress, organ dysfunction, rapidly progressive pulmonary lesions on imaging, or severe intra‐ or extrapulmonary complications. Cases not meeting these criteria were classified as general MPP (GMPP).

Inclusion Criteria

1. MPP was diagnosed by a positive MP-DNA PCR test (from nasopharyngeal swab or bronchoalveolar lavage fluid) and/or a single serum MP antibody titer ≥1:160, combined with compatible clinical and radiological findings. 2. During hospitalization, MPDNA test was positive and underwent testing for macrolide resistance genes; 3. Age < 18 years old; 4. It has complete demographic, clinical data and laboratory data, with no more than 20% of relevant data missing.

Statistical Analysis

The data that conformed to the normal distribution and had uniform variance after normality test and homogeneity of variance test were expressed as mean ± standard deviation (±SD) and compared using t-test. The data that did not conform to the normal distribution or had uneven variance were expressed as median (quartile) [M (P25, P75)] and compared using non-parametric test.

Categorical data are expressed in terms of quantity (percentage), and the chi-square test (X² test or continuous-corrected X² test) is used to compare categorical variables. P value < 0.05 was considered statistically significant. Multivariate Logistic regression analysis was performed and analyzed with IBM SPSS27.0 software.

Results

Research Population

A total of 310 pediatric patients with MPP were included in this study. The cohort comprised 153 males and 157 females (ratio 1:1.03), with a mean age of 6.18 ± 2.58 years. Age distribution was as follows: 8 infants (<1 year), 34 toddlers (1–3 years), 126 preschool children (3–6 years), and 142 school-aged children (6–18 years). Based on susceptibility testing, 231 cases (74.52%) were classified as MRMPP and 79 (25.48%) as Macrolide-susceptible MPP (MSMPP). According to disease severity, 264 cases (85.16%) were SMPP and 46 (14.84%) were GMPP. Temporal distribution showed 98 cases in 2023, 185 in 2024, and 27 in 2025.

Comparison of Clinical Characteristics Between Macrolide-Resistant and Macrolide-Sensitive Mycoplasma pneumoniae Pneumonia

Macrolide-Resistance Gene Positivity Rate of Mycoplasma pneumoniae

The MRMP gene positivity rate was 26.53% (26/98) in 2023, 97.3% (180/185) in 2024, and 92.59% (25/27) in 2025, as shown in Figure 1.

Figure 1.

Macrolide-resistance gene positivity rate of Mycoplasma pneumoniae pneumonia from 2023 to 2025.

Demographics and Clinical Manifestations

The gender distribution showed no significant difference between the MRMPP and MSMPP groups, with 119 females and 112 males in the MRMPP group, compared to 38 females and 41 males in the MSMPP group. Age distribution also did not differ significantly between the two groups: among MRMPP patients, there were 7 infants, 31 toddlers, 92 preschool-aged children, and 101 school-aged children; the MSMPP group included 1 infant, 3 toddlers, 34 preschool-aged children, and 41 school-aged children (both P > 0.05, Figures 2 and 3).

Figure 2.

Comparison of Patient Numbers between Macrolide-Resistant and Macrolide-Sensitive Mycoplasma pneumoniae Pneumonia by Gender.

Figure 3.

Comparison of Patient Numbers between Macrolide-Resistant and Macrolide-Sensitive Mycoplasma pneumoniae Pneumonia across Different Age Groups.

Clinically, cough was present in nearly all enrolled children (99.57%), and fever was equally common in both groups (91%). Although the MRMPP group had shorter hospital stays and fever duration than the MSMPP group, they showed a higher rate of switching to tetracycline antibiotics (eg, doxycycline) and glucocorticoid use. No significant differences were identified in peak body temperature, other clinical manifestations (eg, shortness of breath, moist rales, decreased breath sounds, wheezing), history of allergy, or extrapulmonary complications (P > 0.05, Table 1).

Table 1.

Comparison of Clinical Manifestations Between Macrolide-Resistant and Macrolide-Sensitive Mycoplasma pneumoniae Pneumonia

	MRMPP (n=231)	MSMPP (n=79)	X2/Z	P
Cough	230(99.57%)	79(100%)
Fever	211(91.34%)	72(91.14%)	0.617	>0.05
Short breathing	22(9.52%)	6(7.59%)	0.267	>0.05
The breathing sound on the affected side is reduced	82(35.50%)	20(25.32%)	2.764	>0.05
Moist rales	105 (45.45%)	46(58.23%)	3.844	0.05
Wheezing sound	18(7.93%)	5(6.33%)	0.183	>0.05
History of allergies	73(31.60%)	27(34.18%)	0.179	>0.05
Extrapulmonary damage	49(21.21%)	12(15.19%)	1.351	>0.05
Alternative antibiotics	48(20.78%)	0(0%)	19.423	<0.001*
Glucocorticoid	150(64.76%)	27(34.18%)	22.735	<0.001*
Peak fever (°C)	39.5(39,40)	39.7(39,40)	1.266	>0.05
Duration of fever(days)	5(3,7)	7(5,9)	1.803	0.003*
Hospital stay (days)	9(7,11)	11(8,14)	1.887	0.002*
SMPP	197(85.28%)	67(84.81%)	0.010	>0.05

Note: * P < 0.05.

Auxiliary Examination Findings

Radiologically, the MRMPP group demonstrated significantly higher rates of pulmonary consolidation, atelectasis, and tracheal occlusion on chest imaging, along with a greater incidence of tracheal mucosal erosion and necrosis, compared to the MSMPP group. Laboratory findings further indicated elevated white blood cell count, lactate dehydrogenase (LDH) and significantly higher albumin in the MRMPP group (all P < 0.05).

No significant differences were observed between the two groups in other imaging features (eg, pleural effusion, bronchiectasis, tree-in-bud sign, sputum thrombosis), or in a range of other laboratory parameters, including neutrophil counts and ratios, lymphocyte counts and ratios, procalcitonin (PCT), D-dimer, C-reactive protein (CRP) peak (all P > 0.05; see Tables 2 and 3), among the MRMPP group, there were four cases of pulmonary embolism diagnosed by computed tomography angiography (CTA).

Table 2.

Comparison of Imaging Features Between Macrolide-Resistant and Macrolide-Sensitive Mycoplasma pneumoniae Pneumonia

	MRMPP (n=231)	MSMPP (n=79)	X2	P
Pulmonary consolidation	202(87.45%)	60(75.95%)	5.946	0.015*
Atelectasis	49(21.21%)	8(10.13%)	4.821	0.028*
Pleural effusion	55(23.81%)	18(22.78%)	0.034	>0.05
Tracheal occlusion	61(26.41%)	8(10.13%)	9.017	0.003*
Bronchiectasis	9(3.90%)	3(3.80%)	0.000	>0.05
Tree-in-bud sign	10(4.33%)	7(8.86%)	1.540	>0.05
Pulmonary embolism	4 (1.73%)	0	0.360	>0.05
Sputum plug embolism	53(22.94%)	23(29.11%)	1.211	>0.05
Erosion and necrosis of the tracheal mucosa	29(12.55%)	2(2.53%)	6.570	0.010*

Note: * P < 0.05.

Table 3.

Comparison of Laboratory Parameters Between Macrolide-Resistant and Macrolide-Sensitive Mycoplasma pneumoniae Pneumonia

	MRMPP (n=231)	MSMPP (n=79)	Z/X2	P
White blood cell count (x109/L)	7.85(6.21,9.96)	6.80(5.38,9.35)	1.440	0.032*
Neutrophil count (x109/L)	4.49(3.49,6.42)	4.30(3.09,5.75)	0.878	>0.05
Proportion of neutrophils (%)	61.8(53.3,71.1)	64.7(57.6,69.9)	1.164	>0.05
Lymphocyte count (x109/L)	2.02(1.38,2.63)	1.70(1.29,2.30)	1.184	>0.05
Proportion of lymphocytes (%)	27.3(19.5,35.4)	27(18.7,30.9)	1.256	>0.05
Peak CRP (mg/L)	17.3(6.71,38.4)	24.18(6.5,39.1)	1.046	>0.05
PCT (ng/mL)	0.115(0.076,0.216)	0.1(0.069,0.156)	0.878	>0.05
Albumin (g/L)	40.1(37.8,42.7)	40(37.8,41)	1.435	0.032*
LDH (U/L)	278.2(250.0,330.2)	279.3(260.1,289.1)	1.405	0.039*
D-dimer (mg/L)	0.5(0.3,1.02)	0.54(0.34,1.07)	1.116	>0.05

Note: * P < 0.05.

Multivariate Logistic Regression Analysis of Macrolide Drug-Resistant Mycoplasma pneumoniae Pneumonia in Children

Variables with P < 0.05 in univariate analysis were entered into a multivariate logistic regression model to assess their independent association with MRMPP. The final model identified albumin, pulmonary consolidation, and tracheal occlusion as independent risk factors for MRMPP (Table 4).

Table 4.

Multivariate Logistic Regression Analysis of Risk Factors for Macrolide-Resistant Mycoplasma pneumoniae Pneumonia in Children

	B	SE	SIG	OR	95%CI
Pulmonary consolidation	0.860	0.359	0.017	2.364	1.170–4.775
Tracheal occlusion	1.032	0.418	0.014	2.807	1.237–6.372
Albumin	0.095	0.044	0.032	1.100	1.008–1.200

Discussion

Our study revealed that the macrolide resistance gene positivity rate peaked at 97.3% in 2024. Clinically, MRMPP patients showed shorter fever and hospital stay but more severe radiological findings, and we identified albumin, consolidation, and tracheal occlusion as independent risk factors. Since 2023, a significant global pandemic of MP has emerged, with pronounced outbreaks in East Asia. Studies report a prevalence of 60–70% in China during the late stages of the COVID-19 pandemic, while global data indicate stark regional differences in MRMP rates - 2.02% in Europe compared to 71.22% in Asia during 2023–2024.^7,8 The rising incidence of MPP and MRMP has considerably challenged clinical management in pediatrics. In this context, we conducted a study summarizing the clinical characteristics and risk factors for MRMPP among children in Chengdu, China, who underwent testing for macrolide resistance genes between February 2023 and May 2025. Our detailed comparison between the two groups further confirmed these patterns, with no significant differences in demographics but consistent disparities in clinical and radiological profiles. The macrolide resistance gene positivity rate in our cohort was also consistent with findings from previous regional study.⁹ The rising prevalence of MRMP is likely driven by multiple interacting factors. Surveillance data from Japan illustrate this complexity: the macrolide resistance gene positivity rate fluctuated substantially, dropping from 56.3% in 2015 to 11.3% by 2020, before rebounding to approximately 37.7% in subsequent years.^10,11 This non-linear trajectory suggests that resistance rates are not simply increasing in a monotonic fashion but are instead influenced by a combination of factors, including shifts in circulating strains and changes in antibiotic stewardship policies. This study compared the clinical profiles of children with MRMPP and MSMPP. No significant differences were observed in gender or age distribution between the two groups, and nearly all patients presented with cough and fever. However, children with MSMPP had a longer duration of fever and hospitalization than those with MRMPP, and also exhibited more prominent moist rales on pulmonary auscultation. In contrast, children with MRMPP showed more severe radiological manifestations, including higher frequencies of pulmonary consolidation, atelectasis, and tracheal occlusion. Notably, in contrast to previous reports which suggested longer febrile periods and hospital stays in MRMPP,¹² our findings indicate the opposite trend. However, the shorter durations observed in the MRMPP group are likely attributable to their more severe radiographic presentations. Pronounced imaging abnormalities prompted earlier and more frequent interventions in these children, including switches to alternative antibiotics, administration of glucocorticoids, and performance of bronchoalveolar lavage. Early antibiotic adjustment, immunomodulatory therapy, and bronchoalveolar lavage have all been shown to shorten the overall disease course. Therefore, the shorter fever duration and hospital stay in MRMPP are not due to milder disease, but rather to more aggressive early interventions triggered by imaging severity.^13–15 In addition to the difference in treatment intensity, we also observed more severe airway structural damage in the MRMPP group, manifested as higher rates of tracheal erosion and necrosis, consistent with previous reports.¹⁶ Macrolide resistance prevents the effective clearance of MP, leading to persistent infection. The pathogen can directly damage respiratory epithelial cells through adhesion and the release of virulence factors such as the community-acquired respiratory distress syndrome (CARDS) toxin. Consequently, prolonged infection results in cumulative injury, ultimately causing extensive epithelial shedding, erosion, and necrosis.¹⁷ Furthermore, MP can trigger excessive and sustained immune activation. In our study, the MRMPP group exhibited elevated white blood cell count compared to the MSMPP group. Previous research supports this, demonstrating higher loads of MPDNA in the bronchoalveolar lavage fluid of MRMPP patients, with MPDNA load showing a positive correlation with pro-inflammatory cytokine levels such as IL-1β and IL-6.^18,19 These findings indicate that a high MPDNA load in MRMPP can trigger a disproportionately intense immune response. While aimed at pathogen clearance, the subsequent release of inflammatory mediators also causes collateral damage to respiratory tissues, increasing vascular permeability, promoting tissue edema, and facilitating extensive inflammatory cell infiltration—all of which collectively contribute to mucosal structural injury.^20,21 Furthermore, persistent MRMP infection can perpetuate this inflammatory state, leading to prolonged airway damage and the observed erosion and necrosis. Multivariate logistic regression identified albumin, pulmonary consolidation, and tracheal occlusion as independent risk factors for MRMPP. These factors may reflect more pronounced CARDS toxin expression in MRMPP patients, as suggested in earlier studies.²²

Pulmonary embolism is a rare complication of MP infection. Previous studies have shown that children with MPP have a higher risk of thrombosis.²³ In our study, all four children with MPP and pulmonary embolism exhibited macrolide resistance, with antibody titers of 1:1280. Laboratory findings showed high neutrophil ratios, elevated CRP, and low albumin levels, indicating immune system dysfunction. Elevated D-dimer suggested a hypercoagulable state following MP infection, but this condition improved after standard anti-infective and anticoagulant therapy, and no deaths occurred. These findings suggest that persistent MP infection and prolonged excessive immune responses caused by MRMP infection may increase the probability of thrombosis in MP infection.

In this study, comparison between the MRMPP and MSMPP groups revealed that the presence of macrolide resistance genes was not significantly associated with the severity of MPP. This apparent discrepancy can be explained by the fact that MRMPP leads to persistent local infection and chronic airway inflammation, but the progression to SMPP is predominantly driven by the host’s excessive immune response, such as cytokine storm (TNF-α, IL-1, IL-6), rather than by the resistance mutation per se. Therefore, the mere presence of macrolide resistance genes does not equate to increased virulence or higher risk of severe disease; host immune status and timely therapeutic intervention play equally critical roles. Currently, whether MRMP infection increases the risk of SMPP remains controversial. While some previous studies have reported that MRMP infection can lead to severe pneumonia, others are consistent with our findings, suggesting no significant difference in the incidence of severe pneumonia attributable to MRMP infection.^24,25 This study found that the proportion of children with MRMPP who received alternative. Antibiotics or glucocorticoids was significantly higher than that in the MSMPP group. Secondly, given the difficulty of MP culture, it has become extremely challenging to use antimicrobial susceptibility testing as a clinical diagnostic criterion. Therefore, in current clinical practice, MP infections in which macrolide resistance genes are detected are generally considered MRMP infections.^26,27 Collectively, the above factors may lead to overdiagnosis of MRMP infection. In contrast to other bacteria, macrolide resistance gene mutations in MP do not enhance its virulence nor alter its strongly self-limiting nature. In SMPP cases, excessive immune system activation is common, leading to the massive release of inflammatory mediators such as TNF-α, IL-1, and IL-6 at levels far exceeding the normal range, which may ultimately culminate in a “cytokine storm”. These potent pyrogens continuously stimulate the brain’s thermoregulatory center, resulting in prolonged and intensified fever responses. Concurrently, the overly activated immune response promotes substantial infiltration of inflammatory cells and fibrin into the alveolar spaces. Meanwhile, the CARDS toxin produced by MP directly damages lung epithelial cells. Together, these mechanisms give rise to severe clinical and radiological manifestations.²⁸ Therefore, whether the immune response induced by MP infection progresses to severe pneumonia as a result of macrolide resistance gene mutations is also influenced by the child’s own immune status and other factors.^29,30 Thus, in clinical practice, diagnosing MRMP infection solely on the basis of a positive macrolide resistance gene is overly simplistic. The presence of this gene should not automatically lead to the withdrawal of macrolide drugs. Rather, close monitoring of clinical manifestations during the first 72 hours of treatment is essential. If no substantial improvement occurs, prompt transition to a second-line regimen and augmentation of systemic anti-inflammatory treatment are warranted. However, this observation may be confounded by treatment differences.

This study has several limitations that should be considered when interpreting the results. We acknowledge that treatment decisions were influenced by physician judgment and ward routines, which may introduce bias, and this confounding effect limits causal attribution of the outcomes to resistance alone. First, its single-center design may limit the generalizability of the findings, as the patient population from one institution may not fully represent those from other geographic or clinical settings. Second, the relatively small sample size in the GMPP subgroup may have reduced the statistical power to detect actual differences between groups. These constraints suggest that the conclusions drawn should be viewed with caution, and further multi-center studies with larger sample sizes are warranted to validate our findings.

Conclusion

This study, by analyzing the clinical features and risk factors of MRMPP, confirms that the host immune response plays a critical role in the pathogenicity of resistant strains and the progression to severe disease. These findings underscore the importance of integrating drug resistance monitoring with imaging and bronchoscopic evaluation in the clinical management of MPP. Such a comprehensive approach aids in optimizing treatment strategies—including the timely administration of tetracyclines or glucocorticoids, and ultimately improving patient outcomes. Moreover, both in clinical practice and future research, resistance profiles should not be interpreted in isolation but rather assessed within a broader clinical context. This holistic perspective is essential for the early identification of critical cases and the implementation of timely, effective interventions. Nevertheless, the observed differences in fever duration and hospital stay may be confounded by treatment strategies, and thus the independent effect of macrolide resistance on these outcomes cannot be firmly established.

Funding Statement

This work was supported by Sichuan Province Maternal and Child Medical Science and Technology Innovation Project (2024FX03) and Chengdu Municipal Science and Technology program (2024-YF05-00749-SN).

Abbreviations

MP, Mycoplasma pneumoniae; MPP, Mycoplasma pneumoniae pneumonia; SMPP, severe Mycoplasma pneumoniae pneumonia; GMPP, general Mycoplasma pneumoniae pneumonia; MRMP, macrolide-resistant Mycoplasma pneumoniae; MRMPP, macrolide-resistant Mycoplasma pneumoniae pneumonia; MSMPP, Macrolide-susceptible Mycoplasma pneumoniae pneumonia; CAP, community-acquired pneumonia; CRP, C-reactive protein; CTA, computed tomography angiography; CARDS, community-acquired respiratory distress syndrome; LDH, lactate dehydrogenase; PCT, procalcitonin.

Data Sharing Statement

Due to the requirements of the Ethics Committee of the Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, the datasets generated and/or analyzed during the current research period are not publicly available, but can be obtained from the corresponding author upon reasonable request.

Ethics Approval and Consent to Participate

The study was approved by the Ethics Committee of the Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China (Document number: 2024(124)) and was conducted in compliance with the principles of the Declaration of Helsinki. As this study was retrospective and did not involve clinical intervention in patients, the Ethics Committee of the Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China waived the requirement for informed consent. The data were anonymized and de-identified to protect patient privacy, and confidentiality was maintained throughout the study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.