Case Report: Omadacycline in the treatment of macrolide-unresponsive Mycoplasma pneumoniae pneumonia in an adolescent patient

Omadacycline is a novel tetracycline antibiotic that exhibits good in vitro antibacterial activity against atypical pathogens such as Mycoplasma pneumoniae. It is approved for the treatment of adults with community-acquired bacterial pneumonia. However, the safety and efficacy of omadacycline in pediatric patients under 18 years of age have not yet been established. In the present paper, we report a case of pediatric community-acquired pneumonia in which initial empirical anti-infective therapy had failed. The patient received empirical anti-infective therapy with azithromycin and other antimicrobial agents upon admission but showed a poor clinical response and developed secondary tinnitus and liver dysfunction. After the confirmation of M. pneumoniae infection through metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid, an antibiotic switch to omadacycline was made. Thereafter, the patient’s condition improved, and no adverse reactions were observed. These findings demonstrate that mNGS enables the identification of infection-causing pathogens in patients with unresponsive pneumonia. Omadacycline can be considered as an alternative option for anti-infective therapy in pediatric M. pneumoniae pneumonia, especially when the presence of bacterial resistance, adverse drug reactions, or organ failure are taken into consideration.


Introduction
Mycoplasma pneumoniae is the main pathogen that causes pediatric communityacquired pneumonia.However, given the lack of specificity in clinical manifestations and imaging features and difficulty in obtaining accurate etiological evidence in a timely manner, the diagnosis is often delayed or missed (Huang et al., 2021;Tsai et al., 2021).
Research has found that poor outcomes in patients are associated with delayed diagnosis and inappropriate initial treatment.Therefore, early identification of M. pneumoniae infection and timely administration of targeted treatment are key to reducing the mortality rate (Tong et al., 2022).
Macrolide antibiotics are currently the first-choice treatment for pediatric M. pneumoniae pneumonia.However, there are certain issues associated with these drugs, including bacterial resistance, adverse drug reactions, and restricted use in patients with organ dysfunction (Chen et al., 2020;Vanoverschelde et al., 2021).Omadacycline is a novel semi-synthetic tetracycline that exhibits good in vitro antibacterial activity against atypical pathogens such as Mycoplasma, Chlamydia, and Legionella.It is a potential choice for anti-infective therapy in pediatric M. pneumoniae pneumonia (Burgos and Rodvold, 2019).However, few cases examining this use have been reported.We present herein a case of pediatric M. pneumoniae pneumonia that was unresponsive to initial macrolide treatment but exhibited improvement after treatment with omadacycline.

Case description
A 16-year-old boy was admitted to Huizhou First People's Hospital on Apr 11, 2022, due to fever and coughing that persisted for 1 week.He developed a fever after cold exposure 1 week prior to admission, with the maximum body temperature being 40.0°C.Other symptoms included chills and headache accompanied by severe paroxysmal cough with a small amount of yellow sputum.The patient self-administered oral cefaclor and paracetamol for 3 days, but the high fever persisted, and the cough worsened.Three days before admission, the patient sought medical consultation at the fever clinic of Huizhou First People's Hospital.Routine blood work showed a white blood cell (WBC) count of 5.7*10^9/L and neutrophil ratio of 59.1%.Chest computed tomography (CT) revealed patchy consolidation in the lower lobe of the right lung (Figures 1A-C).The patient was subsequently hospitalized when intravenous ceftriaxone did not resolve the fever.He had been previously healthy with no history of infectious diseases, such as hepatitis or tuberculosis, recent contact with poultry, or recent travel history.
Physical examination results were as follows: body temperature: 38.2°C; pulse: 72 beats per minute; respiration: 24 breaths/min; blood pressure: 108/70 mmHg (1 mmHg=0.133kPa).The patient was alert and oriented and provided relevant responses to questioning.No cyanosis in the mouth or lips, yellow discoloration of the skin or sclera, rash, subcutaneous bleeding, or palpable superficial lymph nodes were observed.Coarse breath sounds were heard in both lungs, but neither dry nor moist rales were detected.No other significant abnormalities were observed.Laboratory test results were as follows: coronavirus disease 2019 RNA and antigen tests, influenza A and B virus antigen tests, and dengue virus antigen test: negative; serum 1,3-b-D-glucan assay, galactomannan assay, Widal test, and Weil-Felix reaction: negative; thyroid function, antinuclear antibody spectrum, and antineutrophil cytoplasmic antibodies: negative; sputum, blood, and midstream urine cultures: negative; ELISA for immunoglobulin M antibodies against Legionella pneumophila, M. pneumoniae, Chlamydia pneumoniae, adenovirus, respiratory syncytial virus, influenza A virus, influenza B virus, and parainfluenza virus in the respiratory tract: negative.Table 1 shows the results of other laboratory tests.
Upon hospitalization, the patient was diagnosed with community-acquired pneumonia.Empirical anti-infective therapy using azithromycin and oseltamivir and symptomatic treatment were concurrently administered.After 72 hours, the patient's body temperature remained above 38.0°Cand the severity of cough and sputum production increased; The expectorated sputum had a white, viscous appearance.The patient also developed bilateral tinnitus and hearing loss.Because adverse reactions to azithromycin could not be excluded, azithromycin was discontinued and piperacillin sodium/ sulbactam sodium was administered as anti-infective therapy.On Day 4 of hospitalization, follow-up examination showed liver dysfunction and an increase in inflammatory markers (Table 1).
Follow-up chest CT showed that the original consolidation in the lower lobe of the right lung had increased in size, with new patchy consolidations in the bilateral lower lobes (Figures 1D-F).These findings demonstrated that the initial anti-infective therapy had failed, with the etiology being unclear.Fiberoptic bronchoscopy was performed on Day 4 and revealed the presence of bronchial mucosa with edema and tracheal hyperemia, with some white secretions in the segmental bronchi.(Figures 2A-F).The mucus was removed by suctioning, and 10 mL of bronchoalveolar lavage fluid was collected for metagenomic next-generation sequencing (mNGS), which was performed using a DA8600 proton highthroughput sequencing system (Guangdong Ascendas Gene Technology Co., Ltd.; Zhongshan, Guangdong, China).The reference databases for antimicrobial resistance were Comprehensive Antibiotic Resistance Database (CARD) and Antibiotic Resistance Genes Database (ARDB).mNGS results obtained on Day 5 indicated the presence of M. pneumoniae (sequence number: 7284, coverage: 99%), 113 sequences of 23SrRNA were detected and no resistance genes were detected, therefore, the 23S rRNA sequence was wild-type.Based on a comprehensive analysis of the patient's clinical presentations, etiological test results, and response to initial treatment, a diagnosis of macrolide-unresponsive M. pneumoniae pneumonia (MUMPP) was made (Chen et al., 2021).As the patient was an adolescent and had developed liver dysfunction, the anti-infective drug was changed to omadacycline (initial dose of 200 mg by intravenous infusion, followed by a dose of 100 mg by intravenous infusion once daily).Three days later, the body temperature returned to normal, and the patient showed an improvement in cough and sputum production.Tinnitus had resolved, and normal hearing had been restored.A follow-up examination indicated a significant improvement in inflammatory markers and various organ function indicators (Table 1).The intravenous infusion of omadacycline was continued for 1 week.On Day 15, a follow-up physical examination showed that the inflammatory markers and organ function indicators had returned to normal, and the follow-up chest CT examination revealed significant resolution of the bilateral lung lesions (Figures 1G-I).Omadacycline was discontinued, and the patient was discharged the following day (Figure 3).One month after discharge, the patient's general condition was satisfactory with an occasional cough, absence of breathing difficulties and tinnitus, and a normal hearing test result.

Discussion
M. pneumoniae pneumonia, an acute infectious disease of the lower respiratory tract, primarily affects children and adolescents.After entering the human body through the respiratory tract, M. pneumoniae can cause direct damage to the respiratory tract epithelium through adhesion and cytotoxic effects.It can also induce pneumonia and other forms of systemic damage through immune mechanisms, with disease severity ranging from asymptomatic to severe.Clinical manifestations, laboratory tests, and imaging characteristics often lack specificity (Kutty et al., 2019;Tsai et al., 2021).The Japan Respiratory Society proposed a clinically based scoring method to aid the rapid diagnosis of M. pneumoniae pneumonia based on six criteria: (1) age < 60 years; (2) no or mild comorbidity; (3) paroxysmal cough; (4) no significant abnormalities on lung auscultation; (5) no expectoration or an absence of other pathogens as shown by Gram staining and rapid urine antigen testing; (6) peripheral blood WBC count < 10*10^9/L.Each criterion carries 1 point.If four of the six criteria or three of the first five criteria are met, there is a possibility of M. pneumoniae infection (Miyashita et al., 2006;Yin et al., 2012).Five out of these six criteria were met in the present case, confirming that the Japan Respiratory Society rapid scoring method enables early identification of M. pneumoniae infection.The imaging presentations of M. pneumoniae pneumonia are complex and varied.Characteristic features include bronchovascular bundle thickening, centrilobular nodules, and ground-glass opacities.However, lung consolidations, which are often overlooked, are the only imaging manifestation in certain patients (Miyashita et al., 2009;Izumikawa et al., 2014).In the present case, the fact that lung consolidation was the main imaging presentation and that other characteristic signs of M. pneumoniae pneumonia were absent may have been the major reason for delayed diagnosis.
Currently, the diagnosis of M. pneumoniae infection primarily relies on serological and polymerase chain reaction (PCR) testing.However, serological tests are time-consuming and cannot provide an early diagnosis, which make them more suitable for retrospective analysis.PCR is highly sensitive and specific; however, it may yield Bronchoscopy findings for an adolescent patient with macrolide-unresponsive Mycoplasma pneumoniae pneumonia.(A-F) Bronchoscopy shows bronchial mucosa with edema and tracheal hyperemia, with some white secretions in the segmental bronchi.
false-positive or false-negative results (Leal et al., 2020;Tang et al., 2021).mNGS is a high-throughput sequencing technology that enables rapid and unbiased detection of various pathogenic microorganisms through shotgun sequencing of nucleic acids from clinical samples (Li et al., 2021).In the present case, initial treatment failed, which led to the suspicion of unresponsive pneumonia.mNGS enabled the identification of M. pneumoniae infection in a timely manner, thereby providing a direction for precise anti-infective therapy and avoiding further deterioration of the patient's condition and antimicrobial misuse.A study by Wang et al. (Wang et al., 2020) on children with severe unresponsive pneumonia showed mNGS provided better sensitivity and accuracy than conventional microbiological test methods.In general, MUMPP was related to mutations in the 23S ribosomal RNA (rRNA) sequence at potential macrolide binding sites (Tong et al., 2022), however, the presence or absence of 23SrRNA sequence mutations were not directly related to MUMPP (Chen, D. et al., 2021).Although no rRNA gene mutations were detected using CARD and ARDB by mNGS, the patient's condition did not improve after 3 days of treatment with macrolides, and the diagnosis of MUMPP was valid.Macrolides, fluoroquinolones, and tetracyclines are commonly used drugs in the clinical treatment of M. pneumoniae pneumonia (Kutty et al., 2019).Research has shown that M. pneumoniae possesses high resistance to macrolides and is sensitive to fluoroquinolones and tetracyclines (Yin et al., 2017;Wang et al., 2022).However, fluoroquinolones are not recommended for the treatment of pediatric patients, as they may possibly cause cartilage developmental disorders in this population (Chen et al., 2020;Ahn et al., 2021).Therefore, tetracyclines should be the first-line drugs for M. pneumoniae infection in children aged >8 years.In the present case, the patient was aged <18 years, and initial treatment with macrolides was ineffective and resulted in deterioration of liver function; therefore, treatment with doxycycline or minocycline was considered inappropriate.After switching to omadacycline, a novel tetracycline antibiotic, the patient's condition improved without the occurrence of adverse reactions.This suggests omadacycline can be considered an alternative anti-infective agent for the treatment of pediatric M. pneumoniae pneumonia.To our knowledge, no similar cases have been reported in the literature thus far.Omadacycline is the first aminomethylcycline antibiotic successfully approved for clinical use.It possesses the ability to resist drug resistance mechanisms in bacteria such as drug efflux and ribosome protection and exhibits excellent in vitro antibacterial activity against various pathogens, including atypical pathogens, drugresistant Streptococcus pneumoniae, and methicillin-resistant Staphylococcus aureus (Burgos and Rodvold, 2019;Zhanel et al., 2020).Studies have revealed that its therapeutic effects in treating adult community-acquired pneumonia are comparable to those of moxifloxacin (Stets et al., 2019).However, the safety and efficacy of omadacycline in pediatric patients aged 8-18 years remain unclear (Burgos and Rodvold, 2019).M. pneumoniae infection and antiinfective drugs have a high tendency to cause liver and kidney impairment in pediatric patients, as the liver and kidney functions of children are not yet fully developed (Meng et al., 2021).Pharmacokinetic studies have shown that omadacycline is widely distributed in most tissues throughout the body after administration, with high plasma concentrations achieved in lung tissue.Dose adjustments are not necessary for elderly patients or patients with liver or kidney dysfunction, and the drug has few drug-drug interactions (Burgos and Rodvold, 2019;Rodvold et al., 2020;Zhanel et al., 2020).Therefore, omadacycline offers significant advantages when used as an anti-infective agent for refractory pediatric M. pneumoniae pneumonia, especially in cases complicated with liver or kidney failure.

Conclusion
The clinical and imaging manifestations of M. pneumoniae pneumonia lack specificity.Even with the empirical use of macrolide antibiotics, disease progression may still occur, and the possibility of M. pneumoniae infection cannot be ruled out.mNGS FIGURE 1 Chest computed tomography (CT) images of an adolescent patient with macrolide-unresponsive Mycoplasma pneumoniae pneumonia.(A-C) Chest CT 3 days before admission, showing patchy consolidation in the lower lobe of the right lung.(D-F) Chest CT on hospital Day 4, showing that the original consolidation in the lower lobe of the right lung had become enlarged and new patchy consolidations had appeared in the bilateral lower lobes.(G-I) Chest CT on hospital Day 15, showing significant resolution of the bilateral lung lesions.

FIGURE 3
FIGURE 3Timeline showing the progress and treatment of macrolide-unresponsive Mycoplasma pneumoniae pneumonia in an adolescent patient.

TABLE 1
Laboratory test results at different time points for an adolescent patient with macrolide-unresponsive Mycoplasma pneumoniae pneumonia.