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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. [ABSTRACT FROM AUTHOR]

Xiucui Zhang,* Huili Huang,* Jianrong Wang, Bo Wei Department of Infectious Disease, Changzheng Hospital, Navy Medical University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo Wei, Department of infectious disease, Changzheng Hospital, Navy Medical University, Shanghai, People’s Republic of China, Email weibi0816@163.comAbstract: The Hepatorenal Syndrome-Acute Kidney Injury (HRS-AKI) patients infected with methicillin-resistant Staphylococcus aureus (MRSA) urgently require safe and effective treatment options due to their compromised hepatic and renal functions, as well as thrombocytopenia resulting from hypersplenism. In our case, an HRS-AKI patient who underwent continuous renal replacement therapy for fluid overload developed fever with chills. His blood tests indicated elevated C-reactive protein and neutrophils, low platelet count, and bilateral lung infiltrates. Subsequently, his blood culture and catheter culture confirmed a catheter-related MRSA bloodstream infection. To address this complex clinical challenge, a novel oxazolidinone antibiotic, contezolid (800mg orally every 12 hours), was introduced into the patient’s anti-infection regimen. Notably, the patient exhibited remarkable improvements and responded favorably to this treatment. During subsequent follow-up, no recurrence of the infection or drug-related adverse events was observed. The successful utilization of contezolid in this case underscores its potential as a novel therapeutic option for treating MRSA infections in patients with HRS-AKI.Keywords: Hepatorenal syndrome-acute kidney injury, methicillin-resistant Staphylococcus aureus, bloodstream infection, contezolid

Guanglu Jiang,1,* Rongmei Liu,2,* Yi Xue,1 Qiping Ge,2 Lihui Nie,2 Zizheng Lv,2 Zhongshun Kong,2 Jin Shi,2 Hongmei Chen,2 Hua Li,2 Xiaoguang Wu,2 Li Xie,2 Yanhua Song,2 Hairong Huang,1 Mengqiu Gao2 1National Clinical Laboratory on Tuberculosis, Beijing Key Laboratory on Drug-Resistant Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mengqiu Gao; Hairong Huang, Email gaomqwdm@aliyun.com; huanghairong@tb123.orgBackground: Contezolid (CZD) is an analog of Linezolid (LZD) that has demonstrated potent in vitro and in vivo activity against tuberculosis (TB) while presenting a safer side-effect profile. In this study, we evaluated the early bactericidal activity (EBA) of CZD compared to LZD, with LZD serving as a control.Methods: Naive, smear-positive pulmonary TB patients were enrolled and randomly assigned to receive either a 14-day monotherapy regimen of 600 mg LZD once daily (QD) or 800 mg CZD twice daily (BID). Sputum samples were collected daily starting one day before treatment initiation and continuing throughout the treatment period. Each sample was processed for the enumeration of acid-fast bacilli (AFB) colonies, and time-to-positivity (TTP) during MGIT960 liquid culture was recorded.Results: A total of 10 eligible patients were enrolled in each treatment group, although one patient in the CZD group was later excluded from the analysis. The early bactericidal activity (EBA0-14) was 0.08 ± 0.12 log CFU/mL/day (95% CI: − 0.02 to 0.18 CFU/mL/day) in the CZD group, compared to 0.03 ± 0.10 log CFU/mL/day (95% CI: − 0.05 to 0.10 CFU/mL/day) in the LZD group. The increase in time-to-positivity (TTP0-14) was 38.6 ± 43.69 hours (95% CI: − 1.85 to 79 hours) in the CZD group and 27.7 ± 78.21 hours (95% CI: − 28.15 to 83.75 hours) in the LZD group. LZD showed rapid bacterial reduction in sputum during the first two days of treatment, whereas CZD demonstrated superior efficacy after a few days of treatment.Conclusion: 800 mg BID contezolid exhibited comparable efficacy to 600 mg QD LZD in treating pulmonary TB in this EBA study. While CZD showed slower initial bactericidal action compared to LZD, its efficacy surpassed that of LZD after a few days of treatment. Given its similar efficacy and superior safety profile, contezolid may serve as an alternative to linezolid for the treatment of tuberculosis.Keywords: contezolid, linezolid, early bactericidal activity, time-to-positivity

Shuang Zhou,1 Chengqi Xin,2– 5 Wenjuan Liu1 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 2Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 3National Local Joint Engineering Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 4National Genetic Test Center, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 5Liaoning Key Laboratory of Frontier Technology of Stem Cell and Precision Medicine, Dalian Innovation Institute of Stem Cell and Precision Medicine, Dalian, Liaoning, People’s Republic of ChinaCorrespondence: Wenjuan Liu; Chengqi Xin, Email liuwenjuan880424@126.com; chengqixin@126.comAbstract: Staphylococcus aureus is a common pathogen of hematogenous lung abscesses. The increased resistance of S. aureus to antibiotics makes infections difficult to treat, often resulting in a poor prognosis. Therefore, it is important to identify S. aureus infections as early as possible and evaluate its sensitivity and resistance to antibiotics, to formulate an appropriate treatment plan. Oxazolidinone antibiotics exhibit potent antibacterial activity against multidrug-resistant (MDR) S. aureus; however, the adverse effects of linezolid, particularly thrombocytopenia, limit its application. Contezolid may ameliorate the hematologic toxicity associated with linezolid. Here, we report the case of a patient with congenital cerebral hypoplasia who was hospitalized due to fever and multiple abscesses in both lungs. In the context of negative blood culture results, the final diagnosis of MDR S. aureus as the causative agent of hematogenous lung abscess was confirmed using macrogenomic next-generation sequencing (mNGS) and targeted next-generation sequencing (tNGS). The patient was treated with linezolid but developed significant thrombocytopenia, so switching to sequential therapy with contezolid, the patient’s platelet counts returned to normal and his condition improved significantly.Keywords: hematogenous lung abscess, Staphylococcus aureus, linezolid, contezolid, next-generation sequencing, congenital cerebral hypoplasia

Abstract Background Staphylococcus aureus infective endocarditis (IE) in native valves is associated with high mortality rates and is prone to various complications, including embolic strokes, which often result in poor prognoses. Contezolid, a novel oxazolidinone antibiotic, exhibits superior therapeutic efficacy with a reduced risk of hematologic toxicity. However, there are currently no reports on the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) IE accompanied by cerebrovascular complications. Case Presentation We reported a young female patient with MSSA IE accompanied by cerebrovascular complications. She was diagnosed through blood culture, transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), and cranial imaging, but the therapy using piperacillin-tazobactam and vancomycin failed. Therefore, the combination therapy of cefazolin and linezolid was applied, and her body temperature gradually returned to normal, and the infection symptoms were controlled. However, the platelets (PLT) dropped to 114 × 109/L, so contezolid was used as an alternative therapy. Subsequently, the PLT returned to normal. The patient received contezolid therapy for 3 weeks and was free of adverse events during the 2 years of follow-up. Conclusion This was the first case of MSSA IE accompanied by cerebrovascular complications in a young woman, who was successfully treated with an antibiotic regimen containing contezolid, without the need for surgical intervention, demonstrating remarkable efficacy and safety.

Background: Enterococcus faecium (E. faecium) stands as a prominent pathogen contributing to Gram-positive bacterial infections in individuals who have undergone liver transplantation. Case presentation: A 66-year-old male with a three-year history of treated anxiety disorder was admitted to our hospital due to recurrent abdominal distension and oliguria. He was diagnosed with hepatic veno-occlusive disease (HVOD), hepatic failure, pneumonia, renal insufficiency and abdominal ascites. A liver transplantation procedure was performed, but the patient's infection index increased on the first day after surgery. Empirical antibiotic therapy with ceftriaxone and meropenem and preventive antifungal therapy were applied. Sputum culture, blood culture, ascites culture and bronchoalveolar lavage fluid (BALF) next-generation sequencing (NGS), revealed the presence of E. faecium. Given the application of various nephrotoxic immunosuppressive agents after liver transplantation, pre-existing renal insufficiency, severe bone marrow suppression, and a history of anxiety disorder treated with sertraline, contezolid was added for the treatment of the Gram-positive bacterial infection. Sixteen days after surgery, cultures from ascites and sputum yielded negative results for fungi and bacteria. Contezolid was subsequently discontinued without any reported adverse events during follow-up. Conclusion: Treatment with contezolid as the first-line therapy for sepsis and pneumonia caused by E. faecium following liver transplantation has shown satisfactory efficacy and safety. Therefore, contezolid may hold great promise for managing this life-threatening condition.

Yongsheng Zhao,* Xianlei Xin,* Bin Wang, Lei He, Qinghua Zhao, Weizheng Ren Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weizheng Ren; Qinghua Zhao, Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of China, Email rwz301@163.com; zhaoqinghuabj@163.comPurpose: In this paper, we observed the use of contezolid in patients with complex intra-abdominal infections in the intensive care unit of the Hepatobiliary Surgery department at the Chinese PLA General Hospital.Patients and Methods: The study collected data on complex intra-abdominal infections patients who received the antibiotic contezolid between January 2022 and April 2023.Results: Contezolid was administered to 12 patients, including 8 with severe acute pancreatitis, 3 with intra-abdominal infections following abdominal surgery, and 1 with complicated intra-abdominal infection after trauma. Gram-positive bacteria, such as Enterococcus faecium, Enterococcus casseliflavus, Staphylococcus capitis, and Staphylococcus haemo-lytica, were detected in 11 patients. All patients who received contezolid had previously been treated with other anti-Gram-positive agents, including linezolid for 9 patients, teicoplanin for 6 patients, and vancomycin for 3 patients. The treatment with contezolid began 20.0 (15.0, 34.5) days after admission and lasted for 8.0 (6.0, 10.0) days. At the end of the treatment, the patients’ body temperature showed a significant decrease. After concomitant therapy, IL-6 levels decreased, and platelet count increased.Conclusion: Contezolid has shown potential in treating complex intra-abdominal infections caused by Gram-positive bacteria by reducing fever and inflammatory response.Keywords: intra-abdominal infection, contezolid, multiple drug-resistant bacteria, gram-positive bacteria

Yan-Jun Xiong,* Yu Xiao,* Lei Xie, Lei Gao, Yi Han, Peng-Fei Huang, Shuang Liu, Ya-Xue Liang, Hua Wang Department of Tuberculosis, Anhui Provincial Chest Hospital (Anhui Institute of Tuberculosis Control), Hefei, Anhui, 230022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hua Wang, Department of Tuberculosis, Anhui Provincial Chest Hospital (Anhui Institute of Tuberculosis Control), No. 392, Jixi Road, Hefei, Anhui, People’s Republic of China, Tel +86 13395694530, Email 1726553540@qq.comBackground: Linezolid (LZD) is a cornerstone medication in the treatment of drug-resistant tuberculosis (DR-TB). However, it frequently triggers adverse effects such as bone marrow suppression, optic neuropathy, and peripheral neuropathy, all of which can impact treatment outcomes and prognosis. Contezolid (CZD), a novel oxazolidinone antibiotic, exhibits comparable antimicrobial efficacy against Mycobacterium tuberculosis as LZD, but with potentially enhanced safety profiles.Case Presentation: This report presents five cases (Cases 1– 5) of LZD intolerance, wherein CZD served as an effective alternative treatment. In Cases 1– 3, LZD administration resulted in bone marrow suppression, primarily manifested as anemia. Transitioning to CZD therapy led to a rise and stabilization of hemoglobin (HGB) levels in Cases 1– 2, and a return to baseline values in Case 3. In Case 4, CZD treatment alleviated symptoms of LZD-induced peripheral neuritis, although complete resolution was not achieved, hinting at potential irreversibility of this type of peripheral neuropathy. In Case 5, direct CZD anti-TB therapy was initiated for recurrent leukopenia and neutropenia, resulting in no further severe myelosuppression and successful recovery.Conclusion: These case studies suggest that CZD could represent an effective and safe option for anti-TB therapy, especially for patients intolerant to LZD.Keywords: contezolid, linezolid, drug-resistant tuberculosis, myelosuppression, peripheral neuropathy

Weijian Liu,* Liangzi Yang,* Hongjuan Qin, Peize Zhang Department of Pulmonary Medicine and Tuberculosis, The Third People’s Hospital of Shenzhen, Shenzhen, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peize Zhang, Email 82880246@qq.comAbstract: Tuberculosis(TB) is a serious infection that affects transplant recipients, particularly in high TB burden countries. Clinical presentation of these patients is atypical, and the care and management are frequently tricky as multi-drug interaction and intolerable adverse effects. Contezolid, a novel oxazolidinone antibacterial agent, had been demonstrated to be effective for TB in vitro and had been shown in some clinical cases with a more favorable safety profile than linezolid, the first-generation oxazolidinone, which had a commonly seen myelosuppression and neuropathy. Additionally, Contezolid has a unique metabolic mechanism that leads to less drug interaction. Here, we report a case of multi-system TB in a transplant recipient with chronic kidney allograft dysfunction. She was intolerant to most first and second-line anti-TB drugs and repeatedly developed ascites and nocturnal low-grade fever. She finally achieved good efficacy and safety results after enhanced anti-TB treatment with the addition of contezolid. Given the increased risk of TB in patients with organ transplantation and multi-drug interaction in patients with severe comorbidities, further clinical studies are needed to investigate the application and appropriate dosage of contezolid in patients with active TB.Keywords: tuberculosis, contezolid, kidney dysfunction, kidney transplantation, tuberculous peritonitis

Xiaoqing Ma,* Ruoying Zhang,* Xinjun Cai, Yuying Lang, Huaichong Wang, Jinmeng Li Department of Pharmacy, Hangzhou Red Cross Hospital, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinmeng Li, Department of Pharmacy, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang Province, 310000, People’s Republic of China, Email jinmeng608@163.comAbstract: As a new generation of oxazolidinone antibacterial drugs, contezolid has been shown to have comparable or even stronger activity than linezolid and has a low risk of adverse reactions such as bone marrow suppression toxicity. However, there are currently very few clinical reports and pharmacokinetic data of contezolid on the anti-tuberculosis therapy. Therefore, we report a case study of the pharmacokinetic study of contezolid in elderly patients with renal insufficiency and tuberculosis. The patient’s condition improved after receiving an anti-tuberculosis regimen containing contezolid, with significant absorption of pleural effusion and lung plaques and nodules reduced. During the treatment, the patients’ platelet and white blood cell levels fluctuated within normal ranges, but hemoglobin levels significantly decreased and did not recover after discontinuation of contezolid. The trough concentration of contezolid and the concentration at 2, 4, 6, and 10 h after administration were 1.27μg/mL, 3.88μg/mL, 6.32μg/mL, 8.99μg/mL, and 3.14μg/mL, respectively. The plasma concentrations of bedaquiline and cycloserine during the treatment were also monitored. This study demonstrated the efficacy and safety of contezolid in the treatment of multidrug-resistant tuberculosis and analyzed its pharmacokinetic changes in elderly patients with renal insufficiency, providing a reference for the clinical use of contezolid.Keywords: contezolid, tuberculosis, plasma concentration, efficacy, safety

Multidrug-resistant tuberculosis (MDR-TB) is a global health concern. Standard treatment involves the use of linezolid, a repurposed oxazolidinone. It is associated with severe adverse effects, including myelosuppression and mitochondrial toxicity. As such, it is imperative to identify novel alternatives that are better tolerated but equally or more effective. Therefore, this review aims to identify and explore the novel alternative oxazolidinones to potentially replace linezolid in the management of TB. The keywords tuberculosis and oxazolidinones were searched in PubMed to identify eligible compounds. The individual drug compounds were then searched with the term tuberculosis to identify the relevant in vitro, in vivo and clinical studies. The search identified sutezolid, tedizolid, delpazolid, eperezolid, radezolid, contezolid, posizolid and TBI-223, in addition to linezolid. An additional search resulted in 32 preclinical and 21 clinical studies. All novel oxazolidinones except posizolid and eperezolid resulted in positive preclinical outcomes. Sutezolid and delpazolid completed early phase 2 clinical studies with better safety and equal or superior efficacy. Linezolid is expected to continue as the mainstay therapy, with renewed interest in drug monitoring. Sutezolid, tedizolid, delpazolid and TBI-223 displayed promising preliminary results. Further clinical studies would be required to assess the safety profiles and optimize the dosing regimens. [ABSTRACT FROM AUTHOR]

Purpose: The principal objective of this project was to review and thoroughly examine the chemical characteristics, pharmacological activity, and quantification methods associated with contezolid. Methods: The article was based on published and ongoing preclinical and clinical studies on the application of contezolid. These studies included experiments on the physicochemical properties of contezolid, in vitro antimicrobial research, in vivo antimicrobial research, and clinical trials in various phases. There were no date restrictions on these studies. Results: In June 2021, contezolid was approved for treating complicated skin and soft tissue infections. The structural modification of contezolid has resulted in better efficacy compared to linezolid. It inhibits bacterial growth by preventing the production of the functional 70S initiation complex required to translate bacterial proteins. The current evidence has indicated a substantial decline in myelosuppression and monoamine oxidase inhibition without impairing its antibacterial properties. Contezolid was found to have a more significant safety profile and to be metabolised by flavin monooxygenase 5, reducing the risk of harmful effects due to drug–drug interactions. Adjusting doses is unnecessary for patients with mild to moderate renal or hepatic insufficiency. Conclusion: As an oral oxazolidinone antimicrobial agent, contezolid is effective against multi-drug resistant Gram-positive bacteria. The introduction of contezolid provided a new clinical option. [ABSTRACT FROM AUTHOR]

Xusheng Gao, Caihong Ding, Dan Xie, Qing Wang, Peipei Jiang, Yuyu Wang, Yu Xiong Department of Tuberculosis, Shandong Public Health Clinical Center, Shandong University, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Yu Xiong, Department of Tuberculosis, Shandong Public Health Clinical Center, Shandong University, No. 11, Lieshishan East Road, Licheng District, Jinan, Shandong, People’s Republic of China, Tel +8615589995880, Email yiyiruguo1@163.comBackground: In recent decades, there has been a substantial surge in the incidence of non-tuberculous Mycobacteria (NTM) infections. However, the diagnosis and management of NTM globally present significant challenges, particularly in cases involving Mycobacterium abscessus complex (MABC) infection where effective therapeutic options are limited.Case Presentation: We reported a 38-year-old female patient who was infected with MABC of skin due to “beauty needle” at a beauty salon, with mass on both cheeks, accompanied by redness, and pain, and some of them was ulcered and effused. Puncture pumping pus from bilateral cheek mass for many times, rinsed with “metronidazole”, and oral “cephalosporin” treatment did not work. Therefore, she came to our hospital. MABC was detected in abscess paracentesis pus by nucleic acid mass spectrometry, and was proved by the cultured result of the pus. Thus, the patient was diagnosed as skin MABC infection, and anti-NTM treatment was taken. However, adverse reactions such as tinnitus, hepatotoxicity and neurovirulence occurred during the initial treatment. After adjusting to the contezolid-containing regimen, these adverse reactions improved. After nearly 6 months of treatment, the cheek mass was gradually reduced and the skin ruptures were gradually healed. Follow-up for 10 months showed that the patient’s facial symptoms were significantly improved, and no drug-related adverse reactions happened.Conclusion: This was the first successful case of multiple drug resistance MABC infection of skin treated with contezolid-containing antibiotic management strategies, which exhibited remarkable efficacy and good safety in this intractable disease.Keywords: Mycobacterium abscessus complex, antibiotic therapy, contezolid, Case report

Jun Wang,1 Wenjuan Nie,1 Liping Ma,1 Qiang Li,1 Ruixue Geng,2 Wenhui Shi,1 Naihui Chu1 1Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, People’s Republic of China; 2Tuberculosis Department, The Second Hospital of Hohhot, Hohhot, People’s Republic of ChinaCorrespondence: Naihui Chu; Jun Wang, Department of Tuberculosis, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis & Thoracic Tumor Research Institute, No. 9, Beiguan Street, Tongzhou District, Beijing, 101149, People’s Republic of China, Tel/Fax +86 108 950 9301, Email chunaihui1994@sina.com; wangjunzt@126.comObjective: Linezolid is increasingly used in the treatment of multidrug-resistant (MDR) M. tuberculosis (TB) with good efficacy; however, its clinical use is limited by intolerable adverse events (AEs). This usually results in dose adjustment or even discontinuation. Contezolid is a new oxazolidinone antibiotic with in vitro antibacterial activity against MDR TB equivalent to linezolid, but its safety and efficacy in MDB TB treatment has not been established.Methods: We conducted a retrospective study on 25 TB patients who received both linezolid and contezolid in Beijing Chest Hospital from January 1, 2022, to January 31, 2023. All patients received linezolid-containing anti-TB regimen first and then switched to contezolid-containing regimens due to the intolerable linezolid-related AEs.Results: Most (68%, 17/25) of the patients were diagnosed with RR-TB or MDR-TB. A total of 30 AEs were reported in these patients. About 26.7% (8/30) of the AEs were Grade 3 (severe) in severity. After switching to contezolid-containing anti-TB regimens for at least 1 month, the linezolid-related AEs were resolved or improved in 90% of the cases. Clinical improvement was observed in all patients after treatment with contezolid-containing regimen, with negative results of sputum culture and/or smear for M. tuberculosis in 84% of the patients.Conclusion: Contezolid can be the first choice instead of linezolid to combine with other anti-TB drugs if necessary. Well-designed clinical trials are required to further confirm the safety and efficacy of contezolid in the treatment of TB patients.Keywords: contezolid, safety, outcome, tuberculosis, linezolid

Sheng Zhao, Wei Zhang, Linfei Zhang, Jing Zhang, Jinghang Li, Linjie Si, Yi Ding, Mingke Li, Yuanyuan Song Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, People’s Republic of ChinaCorrespondence: Sheng Zhao, Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, 210029, People’s Republic of China, Tel +86-25-83714511ext 3107, Fax +86-25-83718836, Email drzhaosheng@126.comAbstract: Infective endocarditis (IE) caused by methicillin-resistant Staphylococcus aureus (MRSA) is usually life threatening and difficult to treat. Contezolid is a newly approved oxazolidinone antimicrobial agent showing potent activity against MRSA. We successfully treated a case of refractory IE caused by MRSA with contezolid in a 41-year-old male patient. The patient was admitted due to recurrent fever and chills for more than 10 days. He had chronic renal failure for more than 10 years and under ongoing hemodialysis. The diagnosis of IE was confirmed by echocardiography and positive blood culture of MRSA. Antimicrobial therapy with vancomycin combined with moxifloxacin, and daptomycin combined with cefoperazone-sulbactam failed in the first 27 days. Moreover, the patient had to take oral anticoagulant after removal of tricuspid valve vegetation and tricuspid valve replacement. Contezolid 800 mg was added orally every 12 hours, to replace vancomycin, for its anti-MRSA activity and good safety profile. Temperature normalized after the contezolid add-on treatment for 15 days. No relapse of infection or drug-related adverse reaction was reported at 3-month follow-up since the diagnosis of IE. This successful experience serves as motivation for a well-designed clinical trial to confirm the utility of contezolid in managing IE.Keywords: infective endocarditis, methicillin-resistantStaphylococcus aureus, contezolid, chronic renal failure

BackgroundInitial choices of antimicrobial therapy for most cases of community-acquired pneumonia (CAP) in children under 5 years of age are typically based on local epidemiology, risk factors assessment, and subsequent clinical parameters and positive cultures, which can lead to the underdiagnosis and underestimation of lung infections caused by uncommon pathogens. Contezolid, an orally administered oxazolidinone antibiotic, gained approval from the National Medical Products Administration (NMPA) of China in June 2021 for managing complicated skin and soft tissue infections (cSSTI) caused by staphylococcus aureus (SA), streptococcus pyogenes, or streptococcus agalactis. Owing to its enhanced safety profile and ongoing clinical progress, the scope of contezolid's clinical application continues to expand, benefiting a growing number of patients with Gram-positive bacterial infections.Case summaryIn this report, we present the first use of contezolid in a toddler with severe CAP caused by SA, aiming to avoid potential adverse drug reactions (ADRs) associated with vancomycin and linezolid.ConclusionAlthough contezolid has not been officially indicated for CAP, it has been shown to be effective and safe in the management of SA-induced severe CAP in this toddler, suggesting its potential as an alternative option in the dilemma, especially for patients who are susceptible or intolerant to ADRs associated with first-line anti-methicillin-resistant staphylococcus aureus (MRSA) antimicrobial agents.

BackgroundContezolid is a novel oxazolidinone antibacterial agent, but there have been no reports of any pertinent clinical studies for the treatment of tuberculosis (TB). This was the first report of three TB patients who were successfully treated with contezolid.Case presentationCase 1 was TB complicated by myelosuppression syndrome. Case 2 was drug-resistant TB complicated by cirrhosis and anemia. Case 3 was drug-resistant TB complicated by liver transplantation that developed severe anemia after linezolid treatment. Following contezolid therapy, the three patients’ symptoms improved significantly, and no adverse reactions were observed. The chest computed tomography (CT) examination also indicated that the therapeutic effect of this anti-TB regimen was as expected.ConclusionContezolid showed good efficacy and fewer side effects in the treatment of TB. It may be a promising TB treatment.

Background: Tuberculosis (TB) is a rare but potentially devastating complication in hematopoietic stem cell transplantation (HSCT) recipients. Myelosuppressionrelated antibiotics should be used cautiously in patients with hematological malignancies, especially those undergoing bone marrow transplantation and receiving bone marrow suppression therapy. Although linezolid has become the recommended drug for severe TB, its hematological toxicity is still an obstacle to its clinical application. Contezolid is a new representative of oxazolidinones in clinical development, showing superior anti-infection efficacy, but there have been no reports on the treatment of post-HSCT TB. Case presentation: We reported a patient with acute lymphoblastic leukemia suffered from pulmonary TB infection after HSCT. During anti-TB treatment, the patient had a poor response to linezolid-containing regimen, and developed side effects such as gingival bleeding and thrombocytopenia, so the administration was switched to contezolid. After 15 days of continuous treatment, the patient's platelet increased to 58×109/L, and he was discharged in stable condition. During subsequent anti-TB treatment with contezolid for more than 7 months, the platelets remained stable, and no hematological adverse reactions and no symptoms of peripheral neuropathy were observed. Moreover, repeat imaging showed that the bilateral lung lesions were significantly reduced, indicating a good outcome for the patient. Conclusion: This was the first successful case of post-HSCT TB patients treated with contezolid-containing antibiotic management strategies, which exhibited remarkable efficacy and good safety in this deadly disease. [ABSTRACT FROM AUTHOR]

Objective To investigate the antibacterial activity of contezolid and linezolid against common Gram-positive bacteria and to preliminarily analyze the mechanism of their inhibition of biofilm. Methods Staphylococcus aureus (S. aureus) and Enterococcus faecalis (E. faecalis) were taken as the research objects. We used the broth dilution method to determine the minimum inhibitory concentration (MIC) of contezolid and linezolid against S. aureus and E. faecalis. The growth curve was used to detect the growth of bacteria under different drug concentrations, and the formation of bacterial biofilm and the survival rate of bacteria in the biofilm were observed by crystal violet staining under the drug concentration that did not inhibit the growth of bacteria. Proteomics was used to screen the differentially expressed proteins in the biofilm of Gram-positive bacteria under the action of contezolid and linezolid. Functional annotation of gene ontology (GO), Kyoto Encylopaedia of Genes and Genomes (KEGG), and protein interaction network (PPI) was used to observe the interaction between proteins. Results Contezolid and linezolid showed broad-spectrum antibacterial activity against S. aureus and E. faecalis, and their MICs were both less than 4 µg/mL. The growth curve showed that contezolid and linezolid at 1/2 × MIC had no effect on bacterial growth. The result of crystal violet staining and the count of viable bacteria in biofilm showed that both drugs could inhibit the formation of S. aureus and E. faecalis biofilm at sub-inhibitory concentration. There were 290 and 222 differentially expressed proteins in the biofilm of Gram-positive bacteria under the action of contezolid and linezolid. The differential proteins mainly involved Rpm, rplE, SasG, Luxs, ald 1, D-alanine aminotransferase, etc. GO analysis showed that the differentially expressed proteins were mainly related to pyruvate metabolism and amino acid metabolism under the action of contezolid. The differential expression of proteins under linezolid mainly involved pyrimidine metabolism, purine metabolism, amino acid metabolism, etc. KEGG analysis showed that the differentially expressed proteins treated with contezolid mainly involved in naphthalene degradation, pyrimidine metabolism, glycolysis, and ribosome excision and repair. The differentially expressed proteins treated with linezolid mainly involved amino acid degradation, fatty acid degradation, purine metabolism, pentose, and glucose phosphate conversion. PPI analysis showed that the differentially expressed proteins under the action of two antibiotics were mainly related to ribosomes. Conclusions Contezolid and linezolid show broad-spectrum antibacterial activity and biofilm inhibition against Grampositive bacteria. These two drugs may inhibit the formation of biofilm of Gram-positive bacteria by inhibiting quorum sensing system, primary metabolism and biofilm formation related genes. [ABSTRACT FROM AUTHOR]

Kaifei Wang, Ye Hu, Zhimei Duan, Han Fu, Xingshuo Hu, Ying Zhao, Ruoxuan Wen, Lina Li, Fei Xie College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Fei Xie, College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, People’s Republic of China, Tel +86-15001028681, Email xielx301@sina.comBackground: Staphylococcus aureus has been well recognized as an important cause of community-acquired pneumonia (CAP), with non-specific characteristics and poor prognosis. In severe CAP (SCAP) guidelines, β-lactam combined with macrolides or fluoroquinolones therapy was recommended, but the efficacy is not satisfactory due to the continued spread of antimicrobial resistance. Contezolid is a new representative of oxazolidinones in clinical development, but no relevant reports have been reported for the treatment of SCAP. This was the first report of a patient with Staphylococcus aureus SCAP who was successfully treated with contezolid combined with other antibiotics and rehabilitation exercise.Case Presentation: A 44-year-old woman with high blood pressure and diabetes was admitted to our hospital owing to cough, sputum, wheezing for 2 weeks, and aggravation for 2 days. The bronchoscopic alveolar lavage and microorganism-Rapid On Site Evaluation (BAL-mROSE) was used to get pathological data, which were positive for Staphylococcus aureus, in line with blood cultures. During hospitalization, the patient received endotracheal intubation for assisted breathing and anti-infective therapy, including meropenem, linezolid, teicoplanin and tazocin successively. Finally, contezolid obtained excellent result, with platelet recovery to normal levels and significant improvement in pulmonary imaging. Meanwhile, the patient’s swallowing disorder improved after continuous rehabilitation exercise. After discharge, she received contezolid consolidation therapy for 1 week and was free of complaints during the 30-day follow-up without any special treatment for SCAP.Discussion: Treatment with contezolid combined with other antibiotics and rehabilitation exercise for SCAP has shown remarkable efficacy and good safety; hence, this regimen is a promising treatment strategy for this fatal disease.Keywords: severe community-acquired pneumonia, methicillin-sensitive Staphylococcus aureus, antibiotic therapy, contezolid, rehabilitation exercise

Objective: To evaluate contezolid (MRX-I) antibacterial activity against Mycobacterium abscessus in vitro and in vivo and to assess whether MRX-I treatment can prolong survival of infected zebrafish. Methods: MRX-I inhibitory activity against M. abscessus in vitro was assessed by injecting MRX-I into zebrafish infected with green fluorescent protein-labelled M. abscessus. Thereafter, infected zebrafish were treated with azithromycin (AZM), linezolid (LZD) or MRX-I then maximum tolerated concentrations (MTCs) of drugs were determined based on M. abscessus growth inhibition using one-way ANOVA. Linear trend analysis of CFU counts and fluorescence intensities (mean ± SE values) was performed to detect linear relationships between MRX-I, AZM and LZD concentrations and these parameters. Results: MRX-I anti-M. abscessus minimum inhibitory concentration (MIC) and MTC were 16 mg/mL and 15.6 mg/mL, respectively. MRX-I MTC-treated zebrafish fluorescence intensities were significantly lower than respective LZD group intensities (whole-body: 439040 ± 3647 vs. 509184 ± 23064, p < 0.01); head: 74147 ± 2175 vs. 95996 ± 8054, p < 0.05). As MRX-I concentration was increased from 0.488 μg/mL to 15.6 μg/mL, zebrafish whole-body, head and heart fluorescence intensities decreased. Statistically insignificant differences between the MRX-I MTC group survival rate (78.33%) vs. corresponding rates of the 62.5 μg/mL-treated AZM MTC group (88.33%, p > 0.05) and the 15.6 μg/mL-treated LZD MTC group (76.67%, p > 0.05) were observed. Conclusion: MRX-I effectively inhibited M. abscessus growth and prolonged zebrafish survival when administered to M. abscessus-infected zebrafish, thus demonstrating that MRX-I holds promise as a clinical treatment for human M. abscessus infections. [ABSTRACT FROM AUTHOR]

ABSTRACT A novel oxazolidinone for the treatment of Mycobacterium tuberculosis has been developed, but the activity of contezolid (MRX-I) still needs to be clarified. In this study, we isolated Mycobacterium tuberculosis from 48 clinical patients with pulmonary tuberculosis. Roche drug susceptibility tests identified drug-sensitive and 39 drug-resistant M. tuberculosis isolates. Drug susceptibility assays indicated that MRX-I exhibited anti-Mycobacterium tuberculosis activity against both drug-sensitive and drug-resistant isolates, with an advantage against drug-resistant isolates. The results also showed that the anti-Mycobacterium tuberculosis activity was comparable to that of linezolid. IMPORTANCE Currently, Mycobacterium tuberculosis has exhibited increased drug resistance, leading to ineffective drug treatment in many patients with tuberculosis. Among the anti-Mycobacterium tuberculosis drugs, oxazolidinones have been gradually developed. Contezolid (MRX-I) has been newly developed in China with advantages versus the first oxazolidinone antibiotic approved by the Food and Drug Administration for clinical use, but the anti-M. tuberculosis activity needs to be further clarified. In this study, in vitro activities of MRX-I against M. tuberculosis were tested. The drug susceptibility assays indicated that MRX-I exhibited anti-M. tuberculosis activity comparable to that of linezolid, with an advantage against drug-resistant isolates.

Tuberculous meningitis (TBM) is the most common form of central nervous system tuberculosis (TB) and the most severe form of extrapulmonary TB. It often presents with non-specific symptoms initially and has a high mortality and disability rate. With good central nervous system penetration, linezolid is recommended for treating drug-resistant, severe, or refractory tuberculous meningitis in China. Despite the benefits of linezolid on TBM treatment, the adverse effects of long-term therapy, such as myelosuppression, peripheral neuritis, and optic neuritis, are notable and can be severe and even life-threatening, leading to discontinuation and compromising treatment expectations. Contezolid is a novel oxazolidinone antibacterial agent approved by the National Medical Products Administration of China in 2021, which has a more favorable safety profile than linezolid in terms of myelosuppression and monoamine oxidase inhibition. Here we first report a case of TBM in a patient who was intolerant to antituberculosis treatment with linezolid and achieved good efficacy and safety results after the compassionate use of contezolid. Given the widespread use of linezolid in TB treatment and the potential risks for long-term use, multi-center prospective controlled clinical trials in TB and TBM patients are needed to investigate the appropriate use of contezolid further.

One of the major limitations in the clinical use of existing oxazolidinone antibiotics is their characteristic adverse reactions, in particular thrombocytopenia. In antiinfective treatment, if patients are suspected of having drug-induced thrombocytopenia, the first step is to immediately discontinue the offending drug. Even in patients with severe infections, the antibacterial drug may need to be changed or the antibacterial treatment may need to be discontinued because thrombocytopenia may have a more serious clinical prognosis. In addition, if the patient needs to continue antibacterial treatment after discharge, the lack of conditions for monitoring platelet levels may also pose hidden dangers to the patient. Contezolid is an orally administered oxazolidinone antibacterial agent approved by the National Medical Products Administration of China in 2021. We found that contezolid may have an improved safety profile with a significantly reduced potential for myelosuppression based on the results of our observational clinical study. In this article, we review the advantages of contezolid as a new oxazolidinone antibiotic and describe three typical clinical cases of patients who experienced drug-induced thrombocytopenia after using linezolid. The platelet levels of these different patients were all significantly improved to varying degrees after initiation of contezolid treatment. [ABSTRACT FROM AUTHOR]

Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally. Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data. Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC0–24h, 106.79 vs. 97.07 h μg/mL) of contezolid even though lower maximum concentration (Cmax, 19.03 vs. 34.49 μg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae0–48h) and renal clearance (CLR) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower Cmax, slightly lower AUC and Ae0–48h of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment. Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment. [ABSTRACT FROM AUTHOR]

Yixin Kang,1,&ast; Cheng Ge,2,&ast; Huan Zhang,3 Saizhe Liu,4 Hongyang Guo,4 Junchang Cui1 1Department of Respiratory Diseases, the First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, 100853, People’s Republic of China; 2Department of Cardiology, the First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, 100853, People’s Republic of China; 3Center of Medicine Clinical Research, the First Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, 100853, People’s Republic of China; 4Department of Cardiology, the Sixth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, 100853, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongyang Guo; Junchang Cui, The First Medical Center, Chinese People’s Liberation Army General Hospital, No. 28 Fuxing Road, Haidian District, Beijing, 100853, People’s Republic of China, Email guohongyang301@126.com; guoguoyoumeng@163.comAbstract: We report the case of an 87-year-old woman with tuberculous pleurisy. She developed adverse effects in the form of thrombocytopenia and gastrointestinal hemorrhage with isoniazid, and thrombocytopenia with linezolid. Her treatment was switched to contezolid plus cycloserine for a 4-week antibiotic duration, with a favorable outcome.Keywords: contezolid, tuberculous pleurisy

Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally.Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data.Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC0–24h, 106.79 vs. 97.07 h μg/mL) of contezolid even though lower maximum concentration (Cmax, 19.03 vs. 34.49 μg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae0–48h) and renal clearance (CLR) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower Cmax, slightly lower AUC and Ae0–48h of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment.Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment.Clinical Trial Registration:https://chinadrugtrials.org.cn, identifier: CTR20171377.

To develop and verify a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining contezolid in plasma and cerebrospinal fluid (CSF). Protein precipitation was performed on samples using linezolid as the internal standard. We used an Agilent EclipsePlus C18 column operating at 0.4 mL/min in conjunction with acetonitrile and water mobile phases for the LC-MS/MS analysis. Using the precursor-product ion pairs 409.15→269.14 (contezolid) and 338.14→195.1 (linezolid), multiple reaction monitoring was used to quantify the compounds. Plasma linearity range was 50.0 to 5000 ng/mL, and CSF was 20.0 to 1000 ng/mL (r2 = 0.999). The inter-batch and intra-batch precisions were ≤2.57% and ≤5.79%, respectively. Plasma recovered 92.94%, and CSF recovered 97.83%. Plasma, CSF, hemolytic plasma, and hyperlipidemic plasma all showed a coefficient of variation ≤ 7.44%. The stability and dilution integrity of this method were also acceptable. The study also demonstrated that artificial CSF can be used as a matrix for the preparation of standard curve samples. A simple and accurate method was developed and validated for the determination of contezolid concentrations in human plasma and CSF, which may be useful for monitoring the therapeutic effect of central nervous system medications. [ABSTRACT FROM AUTHOR]

Contezolid is a novel oxazolidinone, which exhibits potent activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP). In this study, the in vitro activity of contezolid was compared with linezolid (LZD), tigecycline (TGC), teicoplanin (TEC), vancomycin (VA), daptomycin (DAP), and florfenicol (FFC) against MRSA and VRE strains isolated from China. Contezolid revealed considerable activity against MRSA and VRE isolates with MIC90 values of 0.5 and 1.0 μg/mL, respectively. For VRE strains with different resistance genotypes, including vanA- and vanM-type strains, contezolid did not exhibit significantly differential antibacterial activity. Furthermore, the antimicrobial activity of contezolid is similar to or slightly better than that of linezolid against MRSA and VRE strains. Subsequently, the activity of contezolid was tested against strains carrying linezolid resistance genes, including Staphylococcus capitis carrying cfr gene and Enterococcus faecalis carrying optrA gene. The results showed that contezolid exhibited similar antimicrobial efficacy to linezolid against strains with linezolid resistance genes. In general, contezolid may have potential benefits to treat the infections caused by MRSA and VRE pathogens.

Contezolid is a novel oxazolidinone, which exhibits potent activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP). In this study, the in vitro activity of contezolid was compared with linezolid (LZD), tigecycline (TGC), teicoplanin (TEC), vancomycin (VA), daptomycin (DAP), and florfenicol (FFC) against MRSA and VRE strains isolated from China. Contezolid revealed considerable activity against MRSA and VRE isolates with MIC90 values of 0.5 and 1.0 μg/mL, respectively. For VRE strains with different resistance genotypes, including vanA- and vanM-type strains, contezolid did not exhibit significantly differential antibacterial activity. Furthermore, the antimicrobial activity of contezolid is similar to or slightly better than that of linezolid against MRSA and VRE strains. Subsequently, the activity of contezolid was tested against strains carrying linezolid resistance genes, including Staphylococcus capitis carrying cfr gene and Enterococcus faecalis carrying optrA gene. The results showed that contezolid exhibited similar antimicrobial efficacy to linezolid against strains with linezolid resistance genes. In general, contezolid may have potential benefits to treat the infections caused by MRSA and VRE pathogens. [ABSTRACT FROM AUTHOR]

Tuberculosis has become a great global public health threat. Compared with drug-susceptible tuberculosis (TB), the treatment regimens for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) involve more severe adverse events and poorer treatment outcomes. Linezolid (LZD) is the first oxazolidinones used for TB. Thanks to its potent activity against Mycobacterium tuberculosis, LZD has become one of the key agents in the regimens against MDR/XDR-TB. However, this drug may cause intolerability and other adverse events. Contezolid, another novel oxazolidinone, can also inhibit M. tuberculosis, still with fewer adverse effects compared with LZD. This paper is to prospect the potentials of contezolid in the treatment of MDR/XDR-TB, with focus on its efficacy and possible adverse effects. [ABSTRACT FROM AUTHOR]

Contezolid is a novel oxazolidinone antibiotic with a promising safety profile. Oral contezolid and its intravenous (IV) prodrug contezolid acefosamil (CZA) are in development for treatment of diabetic foot and acute bacterial skin and skin structure infections (ABSSSI). The prodrug CZA is converted to active contezolid via intermediate MRX-1352. This study aimed to provide the pharmacokinetic rationale for safe, effective, and flexible dosage regimens with initial IV CZA followed by oral contezolid. We simultaneously modeled plasma concentrations from 110 healthy volunteers and 74 phase 2 patients with ABSSSI via population pharmacokinetics (using the importance sampling estimation algorithm), and optimized dosage regimens by Monte Carlo simulations. This included data on MRX-1352, contezolid, and its metabolite MRX-1320 from 66 healthy volunteers receiving intravenous CZA (150-2400 mg) for up to 28 days, and 74 patients receiving oral contezolid [800 mg every 12 h (q12h)] for 10 days. The apparent total clearance for 800 mg oral contezolid with food was 16.0 L/h (23.4% coefficient of variation) in healthy volunteers and 17.7 L/h (53.8%) in patients. CZA was rapidly converted to MRX-1352, which subsequently transformed to contezolid. The proposed dosage regimen used an IV CZA 2000 mg loading dose with 1000 mg IV CZA q12h as maintenance dose(s), followed by 800 mg oral contezolid q12h (with food). During each 24-h period, Monte Carlo simulations predicted this regimen to achieve consistent areas under the curve of 91.9 mg·h/L (range: 76.3-106 mg·h/L) under all scenarios. Thus, this regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid.IMPORTANCEThis study provides the population pharmacokinetic rationale for the dosage regimen of the intravenous (IV) prodrug contezolid acefosamil (CZA) followed by oral contezolid. We developed the first integrated population model for the pharmacokinetics of the MRX-1352 intermediate prodrug, active contezolid, and its main metabolite MRX-1320 based on data from three clinical studies in healthy volunteers and phase 2 patients. The proposed regimen was predicted to reliably achieve efficacious contezolid exposures independent of timing of switch from IV CZA to oral contezolid., Competing Interests: W.W. is a full time employee of MicuRx Pharmaceuticals Inc., and E.F. and B.H. are former employees of MicuRx. Moreover, J.B.B. and M.E.S. worked as consultants for MicuRx. M.E.S. also served as consultant for Medpace and Basilea, and as speaker for Pfizer Argentina. Further, G.J.A. and J.G.S. received research funding from MicuRx for performing the clinical studies on CZA/contezolid at Worldwide Clinical Trials.

Contezolid is a new oxazolidinone with in vitro and in vivo activity against Mycobacterium tuberculosis comparable to that of linezolid. Pre-clinical and clinical safety studies suggest it may be less toxic than linezolid, making contezolid a potential candidate to replace linezolid in the treatment of drug-resistant tuberculosis. We evaluated the dose-ranging activity of contezolid, alone and in combination with bedaquiline and pretomanid, and compared it with linezolid at similar doses, in an established BALB/c mouse model of tuberculosis. Contezolid had an MIC of 1 µg/mL, similar to linezolid, and exhibited similar bactericidal activity in mice. Contezolid-resistant mutants selected in vitro had 32- to 64-fold increases in contezolid MIC and harbored mutations in the mce3R gene. These mutants did not display cross-resistance to linezolid. Our results indicate that contezolid has the potential to replace linezolid in regimens containing bedaquiline and pretomanid and likely other regimens., Competing Interests: Barry Hafkin is an employee of MicuRx Pharmaceuticals, Khisimuzi Mdluli is an employee of the Bill & Melinda Gates Medical Research Institute, and Nader Fotouhi is an employee of the Global Alliance for Tuberculosis Drug Development.

• Steady-state concentrations of contezolid in serum and cerebrospinal fluid (CSF) were measured in a patient with tuberculous meningoencephalitis. • The observed concentrations in CSF were above the minimum inhibitory concentration of contezolid against Mycobacterium tuberculosis. • The concentrations of contezolid in CSF were close to the estimated serum unbound fraction of contezolid. Central nervous system (CNS) tuberculosis (TB) is a devastating and often life-threatening disease caused by Mycobacterium tuberculosis. Contezolid, a new oxazolidinone, has demonstrated potent antimycobacterial activity in both in-vivo and in-vitro studies, with lower toxicity than linezolid. However, pharmacokinetic data are still not available for contezolid in the CNS of patients with CNS TB. This article reports the steady-state concentrations of contezolid in serum and cerebrospinal fluid (CSF) of a patient receiving contezolid as part of multi-drug treatment for tuberculous meningoencephalitis. At weeks 7 and 11 (7 h post-dose) after initiation of contezolid therapy, the serum concentrations of contezolid were 9.64 mg/L and 9.36 mg/L, respectively. In CSF, the observed concentrations of contezolid were 0.54 mg/L and 1.15 mg/L, respectively. The CSF:serum concentration ratios were 0.056 and 0.123 at weeks 7 and 11, respectively. The observed concentrations in CSF were above the minimum inhibitory concentration of contezolid against M. tuberculosis , and were close to the estimated serum unbound fraction of contezolid (10%), suggesting that unbound contezolid has high CSF permeability. [ABSTRACT FROM AUTHOR]

Contezolid acefosamil (also known as MRX-4), a prodrug of contezolid, is under development for treatment of multidrug-resistant Gram-positive bacterial infections. A phase I single ascending dose (SAD) and multiple-dose placebo-controlled study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of contezolid acefosamil in healthy Chinese subjects following intravenous (IV) and oral administration. Adverse events (AEs) and PK parameters were assessed appropriately. All subjects ( n = 70) completed the trial. Overall, 67 cases of treatment-emergent adverse events (TEAEs) were observed in 49.1% (27 of 55) of the subjects receiving contezolid acefosamil. All TEAEs were mild in severity. No serious AEs or deaths were reported. After IV SAD (500-2,000 mg), the corresponding C of the active drug contezolid increased from 1.95 ± 0.57 to 15.61 ± 4.88 mg/L, AUC max of the active drug contezolid increased from 1.95 ± 0.57 to 15.61 ± 4.88 mg/L, AUC 0-inf from 40.25 ± 10.12 to 129.41 ± 38.30 h·mg/L, median T from 13.33 to 16.74 h. Plasma contezolid reached steady state on day 6 after multiple IV doses, with an accumulation ratio of 2.20-2.96. Oral SAD of 500 and 1,500 mg resulted in contezolid max from 2.00 to 2.75 h, and mean t 1/2 of 2.50 and 2.98 h. Contezolid reached steady state on day 5 after multiple oral doses of 1,500 mg without significant accumulation. Contezolid C max increased with the dose of contezolid acefosamil. The good safety and PK profiles in this SAD and multiple-dose study can support further clinical development of contezolid acefosamil.0-inf of 30.44 ± 7.33 and 162.36 ± 47.08 h·mg/L, and median T max of 2.50 and 2.98 h. Contezolid reached steady state on day 5 after multiple oral doses of 1,500 mg without significant accumulation. Contezolid C max and AUC 0-inf increased with the dose of contezolid acefosamil. The good safety and PK profiles in this SAD and multiple-dose study can support further clinical development of contezolid acefosamil., Competing Interests: Hailin Wang, Hong Yuan and Huahui Yang are full-time employees of Shanghai MicuRx Pharmaceutical Co., Ltd. Other authors declare no competing interests.

Enterococcus faecium ( E. faecium ) is one of the core components of enterococci and causes serious illnesses in the elderly and immunocompromised patients. Due to its adaptive traits and antibiotic resistance, E. faecium has evolved as a worldwide hospital-associated pathogen, especially vancomsycin-resistant Enterococcus faecium (VREfm). Pneumonia caused by VREfm is quite rare in clinical settings, and optimal treatment has not yet been determined. Here, we present a case of nosocomial VREfm pneumonia with lung cavitation following adenovirus infection, which was successfully treated with linezolid and contezolid., Competing Interests: The authors declare no conflict of interest. The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Chen et al.)

Contezolid (MRX-I), a safer antibiotic of the oxazolidinone class, is a promising new antibiotic with potent activity against Mycobacterium tuberculosis (MTB) both in vitro and in vivo . To identify resistance mechanisms of contezolid in MTB, we isolated several in vitro spontaneous contezolid-resistant MTB mutants, which exhibited 16-fold increases in the MIC of contezolid compared with the parent strain but were still unexpectedly susceptible to linezolid. Whole-genome sequencing revealed that most of the contezolid-resistant mutants bore mutations in the mce3R gene, which encodes a transcriptional repressor. The mutations in mce3R led to markedly increased expression of a monooxygenase encoding gene Rv1936. We then characterized Rv1936 as a putative flavin-dependent monooxygenase that catalyzes the degradation of contezolid into its inactive 2,3-dihydropyridin-4-one (DHPO) ring-opened metabolites, thereby conferring drug resistance. While contezolid is an attractive drug candidate with potent antimycobacterial activity and low toxicity, the occurrence of mutations in Mce3R should be considered when designing combination therapy using contezolid for treating tuberculosis.

Contezolid (MRX-I, Youxitai) is an oral oxazolidinone drug being developed by MicuRx Pharmaceutical Co., Ltd., Shanghai, China. It was approved by China's National Medical Products Administration (NMPA) in June 2021, attaining its first approval for the treatment of complicated skin and soft tissue infections (cSSTIs). It is also under clinical development for acute bacterial skin and skin structure infections (ABSSSIs) in the U.S. after receiving qualified infectious disease product (QIDP) classification and fast track status by U.S. Food and Drug Administration (FDA) in September 2018. Contezolid is effective against a broad range of Gram-positive bacteria including activity against methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant Enterococci (VRE). It provides a major benefit over the most popular drug of its class, linezolid (Zyvox), by offering an improved safety profile and minimal effects concerning myelosuppression and monoamine oxidase (MAO) inhibition, two independent adverse events limiting linezolid use in the clinic. The recommended dosage regimen of contezolid is 800 mg every 12 hours for 7-14 days with regular food intake and it can be extended if required. At the mentioned dose under fed conditions, satisfactory efficacy against MRSA with a 90%; or higher cumulative fraction of response and probability of target attainment was achieved. Additionally, contezolid also exhibits activity against Mycobacterium tuberculosis and Mycobacterium abscessus ., (Copyright 2022 Clarivate.)

This study aimed to build a population pharmacokinetic (PopPK) model for contezolid tablet (MRX-I) in healthy subjects and adults with complicated skin and soft-tissue infections (cSSTIs) to further evaluate the efficacy and safety of contezolid and recommend the optimal dosing regimen based on pharmacokinetic/pharmacodynamic (PK/PD) analysis. PopPK analysis was performed using a nonlinear mixed-effects model (NONMEM) to examine the effects of age, body weight, sex, liver and renal functions, albumin, food, dosage strength, and subject type on the PK parameters of contezolid. PK/PD analysis was combined with the MIC of contezolid, clinical/microbiological efficacy, and nonclinical study data. Adverse events (AEs) and study drug-related AEs reported were summarized to examine the relationship between contezolid exposure level and safety measures. A two-compartment model was built. An exponential model was used to describe the interindividual variation. A proportional model was used to describe the intraindividual variation of PK parameters. Good clinical and microbiological efficacy are expected for the infections caused by S. aureus when contezolid is administered at 600 mg or 800 mg every 12 h (q12h). The area under the concentration-time curve from 0 to 24 h at steady state and maximum concentration of drug in serum at steady state of contezolid did not show significant association with the incidence of any AE. The dosing regimen of contezolid at 800 mg q12h administered postprandially for 7 to 14 days is expected to achieve satisfactory clinical and microbiological efficacy in cSSTIs, which is slightly better than that of 600 mg contezolid. This administration has been added to the prescribing information of contezolid tablets.

• Information on analytical methods in biological samples is limited. • Reliable UPLC-MS/MS methods for simultaneous determination of contezolid and M2. • Successful application of the validated assays to a clinical pharmacokinetic study. Contezolid is a novel oxazolidinone antibiotic with good antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus. For the purpose to further characterize the pharmacokinetics of contezolid and its major metabolite M2, accurate and rapid ultra-performance liquid chromatography-tandem mass spectrometric assays (UPLC-MS/MS) were developed and validated for simultaneous quantification of contezolid and M2 in human plasma and urine. The plasma samples were pretreated by liquid–liquid extraction. The automated solid phase extraction method was used to preprocess urine samples. ACQUITY UPLC® BEH C8 (2.1 mm × 100 mm, 1.7 µm) column was used to separate the analytes with a gradient mobile phase of acetonitrile and water at a flow rate of 0.4 mL/min. The calibration curves showed good linearity over the concentration ranges of 0.0100–5.00 µg/mL for contezolid in plasma and urine, 0.00200–1.00 µg/mL in plasma and 0.0200–10.0 µg/mL in urine for M2, respectively. For both plasma and urine assays, the intra- and inter-batch accuracy and precision were within 15% for all quality control levels, including the lower limit of quantitation. The methods were fully validated and successfully applied to a pharmacokinetic study of contezolid tablets in subjects with moderate hepatic impairment. [ABSTRACT FROM AUTHOR]

Contezolid (MRX-I), a novel oxazolidinone antibiotic, was recently approved for the treatment of serious Gram-positive infections. The pharmacokinetics and disposition of [ 14 C]contezolid were investigated in a single-dose human mass balance study. Cross-species comparison of plasma exposure for contezolid and metabolites was performed, and the safety of the disproportionate metabolite in human was evaluated with additional nonclinical studies. After an oral administration of 99.1 μCi/602-mg dose of [ 14 C]contezolid, approximately 91.5% of the radioactivity was recovered in 0 to 168 h postdose, mainly in urine followed by that in feces. The principal metabolic pathway of contezolid in human comprised an oxidative ring opening of the 2,3-dihydropyridin-4-one fragment into polar metabolites MRX445-1 and MRX459, with recovery of approximately 48% and 15% of the dose, respectively, in urine and feces. Contezolid, MRX445-1, and MRX459 accounted for 68.0%, 19.5%, and 4.84% of the plasma exposure of the total radioactivity, respectively. Metabolites MRX445-1 and MRX459 were observed in disproportionately larger amounts in human plasma than in samples from rat or dog, the rodent and nonrodent species, respectively, used for the general nonclinical safety assessment of this molecule. This discrepancy was resolved with additional nonclinical studies, wherein the primary metabolite, MRX445-1, was further characterized. The no-observed-adverse-effect level (NOAEL) of MRX445-1 was determined as 360 mg/kg body weight/day in a 14-day repeat-dose test in pregnant and nonpregnant Sprague Dawley rats. Furthermore, MRX445-1 exhibited no antibacterial activity in vitro . Thus, MRX445-1 is not expected to exert clinically relevant pharmacology and toxicity.

Contezolid (MRX-I), a new oxazolidinone, is an antibiotic in development for treating complicated skin and soft tissue infections caused by resistant Gram-positive bacteria. This was a thorough QT study conducted in 52 healthy subjects who were administered oral contezolid at a therapeutic (800 mg) dose, a supratherapeutic (1,600 mg) dose, placebo, and oral moxifloxacin at 400 mg in four separate treatment periods. The pharmacokinetic profile of contezolid was also evaluated. Time point analysis indicated that the upper bounds of the two-sided 90% confidence interval (CI) for placebo-corrected change-from-baseline QTc (ΔΔQTc) were <10 ms for the contezolid therapeutic dose at each time point. The upper bound of the 90% CI for ΔΔQTc was slightly more than 10 ms with the contezolid supratherapeutic dose at 3 and 4 h postdose, and the prolongation effect on the QT/QTc interval was less than that of the positive control, moxifloxacin, at 400 mg. At 3 and 4 h after the moxifloxacin dose, the moxifloxacin group met the assay sensitivity criteria outlined in ICH Guidance E14 by having a lower confidence bound of ≥5 ms. The results of a linear exposure-response model which were similar to that of a time point analysis demonstrated a slightly positive relationship between contezolid plasma levels and ΔQTcF interval with a slope of 0.227 ms per mg/liter (90% CI, 0.188 to 0.266). In summary, contezolid did not prolong the QT interval at a therapeutic dose and may have a slight effect on QT interval prolongation at a supratherapeutic dose., (Copyright © 2020 American Society for Microbiology.)

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is among the most frequent causative agents of acute bacterial skin and skin-structure infections (ABSSSI) and has been associated with increased risks of invasive disease and of treatment failure., Areas Covered: In this review, we focus on those novel anti-MRSA agents currently in phase I or II of clinical development that may enrich the armamentarium against ABSSSI caused by MRSA in the future., Expert Opinion: Promising agents belonging to either old or novel antibiotic classes are currently in early phases of clinical development and may become available in the future for the effective treatment of ABSSSI caused by MRSA. In particular, the future availability of agents belonging to novel classes will be important for guaranteeing an effective treatment and for allowing outpatient treatment/early discharge, with a consequent reduced impact on healthcare resources. However, this does not mean that we can relax our efforts directed toward improving the responsible use of already available agents. Indeed, preserving their activity in the long term is crucial for optimizing the use of healthcare resources.

This study assessed the tolerability and pharmacokinetic (PK) properties of a new-generation oxazolidinone, contezolid (MRX-I), and its major inactive metabolite, M2, after single oral administrations of 800, 1200, and 1600 mg in the fed state, and compared the efficacy of 3 dosing regimens in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection based on PK/pharmacodynamic (PD) analysis. A Phase I study at a single study center was conducted with 2 parts. In the first part, 20 healthy subjects received a single oral dose of 1200 or 1600 mg of contezolid or placebo in the fed state in a double-blind, placebo-controlled, dose-escalation tolerance study. In the second part of the study, 52 subjects received a single oral dose of 800 mg of contezolid in the fed state in a single-center, randomized, blinded, 4-period, crossover, thorough QT study. Noncompartmental analyses were used to evaluate the PK properties of contezolid and M2. Steady-state concentrations of contezolid following the 3 dosing regimens (800, 1200, and 1600 mg q12h) were simulated by employing a newly developed 2-compartmental PK model. The minimum inhibitory concentration (MIC) distributions of contezolid were analyzed in 178 Staphylococcus , Enterococcus, and Streptococcus clinical isolates. Monte Carlo simulations were conducted to predict the efficacy of the 3 dosing regimens to obtain probability of target attainment and cumulative fraction of response. Single-dose oral administrations of 800, 1200, and 1600 mg of contezolid were well tolerated in healthy subjects in the fed state, and nonlinear PK was observed. The mean plasma exposures to M2 exceeded 17.3% of contezolid exposure in the 3 groups. Both MIC 50 and MIC 90 (MICs that inhibit the growth of 50% and 90% of microorganisms, respectively) of contezolid against MRSA were 1 mg/L with clinical isolates from China. PK/PD analysis and Monte Carlo simulations predicted that 800 mg q12h of oral contezolid would be efficacious against MRSA infection, with a MIC of ≤4 mg/L (probability of target attainment, >90%; cumulative fraction of response, >90%). Contezolid is a well-tolerated treatment option for MRSA infection, including at supratherapeutic doses up to 1600 mg. The regimen of 800 mg q12h could achieve efficacy in treating bacterial infection with MRSA. To our knowledge, this is the first PK study to predict that a dosing regimen of 800 mg q12h of oral contezolid is sufficient for treating MRSA infection, with a MIC of ≤4 mg/L. A Phase III study of this suggested dosing regimen is being conducted. Chinadrugtrials.org.cn identifier: CTR20161074. [ABSTRACT FROM AUTHOR]