ABSTRACT
Polypharmacy in managing severe tuberculosis patients usually poses a risk of adverse drug reactions. Contezolid is a new oxazolidinone antibiotic showing good in vitro and in vivo activity against Mycobacterium tuberculosis . Contezolid add‐on regimen shows promising efficacy and safety results in managing severe tuberculosis patients complicated with acute thrombocytopenia.
Keywords: contezolid, Mycobacterium tuberculosis , thrombocytopenia, treatment outcome, tuberculosis
1. Introduction
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis . The condition of patients may be exacerbated in case of intolerance to first‐line anti‐TB drugs and/or multidrug resistance. For severe TB patients, polypharmacy and combination therapies are inevitable in order to contain M. tuberculosis . However, polypharmacy usually poses risk of adverse drug reactions to patients. Therefore, alternative anti‐TB drugs with satisfactory efficacy and better safety profiles will make a difference in clinical practice.
Contezolid is a novel oxazolidinone antibiotic newly approved for treatment of complicated skin and soft tissue infections in China [1]. It is also active against M. tuberculosis in addition to Gram‐positive bacteria [2]. Compared to linezolid, the first oxazolidinone antibiotic as one of the core anti‐TB drugs in clinical use, contezolid has a better safety profile with significantly reduced potential for myelosuppression and monoamine oxidase inhibition (MAOI). Here we report a case of intractable pulmonary TB in a 32‐year‐old male patient, who was successfully managed by contezolid‐containing combination therapy.
2. Case History/Examination
A 32‐year‐old male experienced fever (up to 38.8°C) and fatigue accidentally in the beginning of September 2021. Pulmonary tuberculosis (TB) was diagnosed by metagenomic next‐generation sequencing (mNGS) analysis of bronchoalveolar lavage fluid (BALF) sample in local hospital. He was then transferred to a TB specialty, where the patient was also found with tuberculous meningitis and pleuritis. The standard HREZ (isoniazid, rifampin, ethambutol, and pyrazinamide) anti‐TB regimen was administered on November 4. Two days later, the patient developed skin rash and acute decrease in platelet count. The anti‐TB regimen was adjusted to amikacin + isoniazid + p‐aminosalicylate sodium + moxifloxacin. The patient was admitted to our department on November 24 because his condition continued to deteriorate.
The physical examination on admission found that the patient was conscious but appeared weak, and unable to get out of bed. Several ecchymosis spots were observed at the site of blood drawing and injection on both arms. A few moist rales were heard over the right lung. His breath sound was low in the left lower lung. M. tuberculosis was identified by mNGS from BALF of the patient on November 2, 2021. Cerebrospinal fluid (CSF) test on November 16, 2021, showed CSF pressure of 16 cm H2O, glucose 3.1 mmol/L, total protein 448 mg/L, chloride 123.5 mmol/L, and C‐reactive protein (CRP) 63.06 mg/L. Magnetic resonance imaging (MRI) of brain on November 12, 2021, revealed abnormal nodules, indicative of tuberculosis. Chest CT on November 13, 2021, showed tuberculosis lesions scattered on bilateral lungs, and tuberculous pleurisy on the left side. Hematology test on November 23 reported platelet count 11.00 × 109/L (thrombocytopenia). Bone marrow tests on December 24 did not identify any distinct hematopoietic abnormality except a fatty bone marrow.
3. Diagnosis and Treatment
The following diagnoses were made on admission: (1) secondary pulmonary TB, upper, middle and lower/upper and lower lobes, smear (−), and treatment‐naive; (2) secondary thrombocytopenia; (3) tuberculous meningitis (clinical diagnosis); (4) left tuberculous pleurisy; and (5) suspected subacute hematogenous pulmonary TB.
After admission, the drugs that may induce thrombocytopenia were discontinued. Contezolid 800 mg was administered orally once daily since November 26 after informed consent of the patient and his family. The platelet count increased steadily after initiation of contezolid therapy (Figure 1). On December 8, isoniazid, moxifloxacin, and amikacin were combined with contezolid to form a stable anti‐TB regimen for long‐term treatment.
FIGURE 1.
Changes in platelet, WBC, and RBC counts over time. PLT, platelet, refer to left Y‐axis scale (×109/L); WBC, white blood cell, refer to right Y‐axis scale (×109/L); RBC, red blood cell, refer to right Y‐axis scale (×1012/L). Contezolid 800 mg once daily was added on November 26.
4. Conclusion and Results
Contezolid combined with isoniazid, moxifloxacin, and amikacin to form a stable anti‐TB regimen achieved success in a TB patient complicated with acute thrombocytopenia. This finding suggests that contezolid may provide an alternative treatment option for severe TB patients complicated with thrombocytopenia.
The patient was followed up for 4 months. Pulmonary symptoms resolved. Chest CT and brain MRI showed improvement in TB lesions (Figure 2). M. tuberculosis was negative in follow‐up testing of sputum sample. Subsequent hepatic and renal function and coagulation tests did not find major adverse events (Figure 3).
FIGURE 2.
CT scan on October 29, 2021, showed patchy infiltrative lesions in both lungs (A1), which were improved and resolved gradually from December 10, 2021 (A2), to February 15, 2022 (A3). The tuberculous nodule identified by brain MRI on November 21, 2021 (A4) shrank apparently on February 23, 2022 (A5). Bone marrow biopsy and histological assay on December 24, 2021, did not find any hematopoietic abnormality (A6).
FIGURE 3.
Clinical course of the patient before and after contezolid treatment. AE, adverse event; BALF, bronchoalveolar lavage fluid; CSF, cerebrospinal fluid; HREZ, isoniazid, rifampin, ethambutol, pyrazinamide; mNGS, metagenomic next‐generation sequencing; MRI, magnetic resonance imaging; TB, tuberculosis.
5. Discussion
Severe infections may lead to decreased platelet count. The progressive decrease of platelets can also predict the ongoing deterioration of disease [3, 4]. It is reported that rifampin, isoniazid, linezolid, and other important anti‐TB drugs can cause thrombocytopenia [5]. The acute thrombocytopenia event in this case may be related to infection, immune‐induced or drug‐induced event. If the patient with severe TB complicated with severe thrombocytopenia or progressive decline of platelets, the drugs that may induce thrombocytopenia should be discontinued to avoid massive hemoptysis and other life‐threatening conditions [6]. Therefore, after careful discussion and informed consent of the patient and his family, contezolid was added after discontinuation of other anti‐TB drugs that were potentially related to thrombocytopenia. When the platelet count recovered to normal level, isoniazid, moxifloxacin, and other drugs were resumed. Meanwhile, gamma globulin was used to guarantee adequate immunity. Treatment switch to contezolid‐containing anti‐TB regimen successfully saved the life of this young patient. After 24‐week treatment, contezolid was suspended for 4 weeks due to the COVID‐19 pandemic in Shanghai. The COVID‐19 outbreak in Shanghai in the spring of 2021 triggered strict control measures in hospitals. The patient was discharged due to the closure of non‐emergency healthcare services. Contezolid treatment was stopped because the condition of the patient was improved and the results of laboratory tests were stable. No drug‐related adverse events were reported during the 24‐week follow‐up.
Contezolid, just like linezolid, belongs to oxazolidinone antimicrobial agents. It has been used in managing the infections caused by Gram‐positive bacterial and mycobacterial infections. Contezolid was an alternative to linezolid to combine with other anti‐TB drugs to address the complicated rifampicin‐resistant or MDR‐TB cases, especially when patients are intolerable to other treatments. The following evidence supports the utility of contezolid in managing complicated TB. Contezolid and linezolid had shown the same in vitro activities against the clinical isolates of M. tuberculosis in China in terms of MIC50 and MIC90. However, contezolid had better intracellular anti‐TB effects than linezolid in terms of reducing the colony‐forming units (CFU) in a dose‐dependent manner [2, 7, 8]. Contezolid has a trifluoride noncoplanar molecular structure, which can minimize its inhibitory effect on bone marrow. Animal experiments and phase III clinical trials have proved that contezolid has minimal effect on platelets [9]. Contezolid treatment may largely avoid the AEs caused by myelosuppression and MAO inhibition, which were reported in the patients receiving long‐term linezolid treatment. Other authors have reported the use of contezolid in successful treatment of tuberculous pleurisy in a patient with a leadless pacemaker. The preliminary experience in this case will encourage us to explore more about the potential utility of contezolid in such complicated TB patients [10].
Author Contributions
Liuqing Zhou: conceptualization, data curation, formal analysis, investigation, methodology, resources, validation, writing – original draft, writing – review and editing. Yimin Wang: conceptualization, data curation, investigation, methodology, resources, validation, visualization, writing – review and editing. Jixue Zhou: conceptualization, data curation, formal analysis, investigation, project administration, resources, supervision, validation, writing – original draft, writing – review and editing.
Ethics Statement
This study was approved by the ethics committee of the 905th Hospital of PLA Navy (approval No.: 2024‐16).
Consent
Written informed consent was obtained from the patient for publication of the de‐identified data and the images in this case report. The patient expressed satisfaction with the treatment effect.
Conflicts of Interest
The authors declare no conflicts of interest.
Funding: The authors received no specific funding for this work.
Liuqing Zhou and Yimin Wang contributed equally to this work and should be considered as the co‐first author.
Data Availability Statement
Data are available upon reasonable request to the corresponding author.
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Associated Data
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Data Availability Statement
Data are available upon reasonable request to the corresponding author.