Early Bactericidal Activity (EBA) Against M. tuberculosis

The objective of the EBA study is to evaluate the antimicrobial activity, with a particular focus on the fast-growing bacilli, during the initial 2 days of therapy (EBA0–2) [24]. However, the extended EBA study measures the antimicrobial activity for the slowly replicating bacilli during days 2 and 7 [25]. In 2010, Diacon et al. further prolonged the EBA study duration to 14 days with the aim of enhancing precision and capturing further data [26]. In China, EBA studies typically adopt a 0- to 14-day study period [27]. Dietze et al. reported that the EBA0–2 of LZD was modest (0.26 log10cfu/ml/day for 600 mg bid and 0.18 log10cfu/ml/day for 600 mg qd) compared to isoniazid (0.67 log10cfu/ml/day for 300 mg qd), but EBA2–7 was minimal (0.04 log10cfu/ml/day for 600 mg bid and 0.09 log10cfu/ml/day for 600 mg qd) when compared to isoniazid (0.16 log10cfu/ml/day for 300 mg qd) [28]. In an EBA study that compared 14-day monotherapy treatments of CZD (800 mg bid) and LZD (600 mg qd), CZD (EBA0–14 0.08 log10cfu/ml/day) exhibited similar efficacy to that of LZD (0.03 log10cfu/ml/day) during the 2-week treatment course. Although the bactericidal activity of CZD was lower than that of LZD during the first few days, CZD surpassed LZD after the first week of treatment [29]. Therefore, regarding the anti-M. tuberculosis activity in the human body, CZD (800 mg bid) is comparable to LZD (600 mg qd). In an EBA study that compared DZD with HRZE and LZD (600 mg bid), the average daily decline in log-CFU of all dosages of DZD ranged from 0.019 to 0.053, figuratively lower than that of HRZE (0.192) and LZD (0.154) [30]. Similarly, the daily decline in log10CFU counts of SZD 600 mg bid and SZD 1200 mg qd was 0.088 and 0.068, respectively, while that of HRZE reached 0.197 [31], consistent with Kim’s results. Therefore, despite the methodological differences between studies, the EBA of CZD appears to be higher (0.08) than that of DZD (0.019–0.053) and SZD 1200 mg qd (0.068), but this observation requires verification in head-to-head studies.

Clinical Utility of CZD in Treating Pulmonary TB (PTB)

In a prospective, randomized, and active-controlled study, a total of 27 patients with DR-PTB were enrolled to explore the safety and tolerability of CZD treatment over a period of 2 months. The study demonstrated that CZD and LZD exhibited comparable efficacy over a 2-month treatment period, while the CZD group displayed significantly fewer adverse events (AEs; 14.3%) than the LZD group (92.3%) [32]. In a retrospective study encompassing 25 patients who received an LZD-containing anti-TB regimen initially and subsequently transitioned to a CZD-containing regimen as a result of LZD intolerance, the LZD-related AEs were resolved or improved in 90% of cases following the switch to CZD for a minimum of 1 month [33]. In addition, clinical improvement was observed in all patients, and 84% of them displayed negative results of sputum culture and/or smear for M. tuberculosis [33]. Recently, another retrospective study investigated the clinical use of CZD in treating patients with complex drug-susceptible (DS) PTB/multiorgan TB. Eleven patients who were intolerant of or had contraindications to standard anti-TB therapy were administered CZD for a period of at least 1 month. No serious AEs were reported, and all patients demonstrated clinical improvement and sputum culture negativity [34]. These studies indicated that CZD could be positioned as a clinically viable alternative to LZD, offering similar efficacy and a superior safety profile in patients with PTB. Currently, head-to-head clinical trials comparing other novel oxazolidinones with LZD or CZD for anti-TB are still lacking. Two phase II dose-finding trials of SZD and DZD demonstrated the potential of these emerging agents for anti-TB regimens combined with bedaquiline, delamanid, and moxifloxacin [35, 36]. While promising, it also requires validation through well-designed comparative prospective clinical trials before any definitive clinical conclusions can be drawn.

A series of case reports have documented the successful treatment of DR-TB with a CZD-containing regimen, notably in patients with complex comorbidities, such as HBV-related liver failure, renal insufficiency, thrombocytopenia, etc. [37,38,39,40,41,42,43,44,45,46]. A summary of these case reports is provided in Supplementary Table 1. In a patient with hematogenous disseminated PTB that caused bronchial TB, tuberculous meningitis, tuberculous polyserositis, hepatic TB, splenic TB, and mediastinal lymph node TB, a first-line anti-TB regimen (isoniazid, pyrazinamide, levofloxacin, and rifampicin) was used. However, as a result of the occurrence of rifampicin-induced drug fever, the treatment was modified to an LZD-containing regimen. Nevertheless, after 7 months of LZD treatment, there was an observed progression of limb numbness. Consequently, the patient was transitioned from LZD to CZD. During the subsequent 1-year period of treatment, no instances of neurotoxicity or hematologic toxicity adverse reactions were observed. Subsequent imaging revealed no pathological findings, sputum cultures confirmed the absence of M. tuberculosis, and antitubercular therapy was stopped as the patient achieved clinical cure [38]. Li et al. reported a case of successful treatment of PTB with CZD in a patient with acute lymphoblastic leukemia [44]. This patient developed PTB after receiving hematopoietic stem cell transplantation. During the course of anti-TB treatment comprising LZD, the patient exhibited an inadequate response, accompanied by the development of thrombocytopenia, with platelet levels declining to 14 × 109/L. Repetitive platelet transfusions proved to be ineffective. Subsequently, LZD was replaced with CZD for the continuation of the anti-TB treatment. Throughout the treatment course containing CZD, no discomfort or AEs were reported, radiology results revealed improvement of lesions, and the platelet count elevated and remained relatively stable at 98 × 109/L, indicating a favorable outcome for this case. Moreover, Wang and Ma reported on three patients with PTB complicated by myelosuppression syndrome, cirrhosis, liver transplantation, and anemia, who were treated with CZD-containing regimens and achieved expected therapeutic effects with no adverse reactions observed [46]. All the aforementioned case reports demonstrate that CZD maintains a satisfactory safety profile for use in patients with specific types of TB, especially those combined with severe comorbidities and complications.

Clinical Practice of CZD in the Treatment of Extrapulmonary Tuberculosis (EPTB)

M. tuberculosis typically infects the lungs, but when the infection extends to other organs, such as the pleura, abdomen, skin, lymph nodes, bones, joints, genitourinary tract, and meninges, it is classified as extrapulmonary tuberculosis (EPTB) [47]. Although most forms of EPTB do not contribute to the transmission of TB, tuberculous meningitis (TBM) and several other forms of EPTB are associated with particularly poor outcomes [48]. In China, a nationwide survey of 6843 patients with TB showed that approximately one-quarter of them had EPTB, with the respiratory, musculoskeletal, and peripheral lymphatic systems being the most commonly affected [49]. Another large-scale epidemiological study in China identified the following three most prevalent EPTB lesions: tuberculous pleurisy (49.8%), bronchial TB (14.8%), and TBM (7.6%) [50]. It is evident that EPTB also poses a significant public health challenge in China.

The treatment of TBM remains fundamentally consistent with that of PTB, albeit with extended treatment duration. In the “WHO consolidated guidelines on tuberculosis Module 4: Treatment and care,” [51] LZD is listed as a potential treatment option for MDR/RR-TBM, citing its high penetration in cerebrospinal fluid (CSF) as a key factor in its efficacy. Abdelgawad et al. reported that the CSF–plasma partition coefficient of LZD co-administered with rifampicin can reach 37% [52]. A phase 2a trial enrolled 52 patients with HIV-associated TBM and randomly assigned them to one of three groups: arm 1 received standard of care (HRZE regimen), arm 2 added LZD and a higher dose of rifampicin as per arm 1, and arm 3 added aspirin as per arm 2. The study revealed that the efficacy was comparable across the groups; however, the outcome was suboptimal in arm 3 [53]. The safety of high-dose rifampicin and adjunctive LZD in combination with the standard of care for HIV-associated TBM can be confirmed, but further research is necessary to ascertain whether the potential toxicity associated with these interventions, particularly high-dose aspirin, outweighs the benefits. It is encouraging to note that several clinical trials of high-dose rifampicin and LZD are ongoing (NCT04021121, NCT03537495, NCT04145258). At present, the utilization of CZD in the context of CNS tuberculosis has been documented in case reports. Xu et al. presented a case of TBM in a patient intolerant to LZD-containing anti-TB therapy, who demonstrated favorable efficacy and safety outcomes following compassionate use of CZD (400 mg, bid, po) combined with isoniazid (0.6 g, qd, po), ethambutol (0.75 g, qd, po), levofloxacin (0.6 g, qd, po), and cycloserine (0.25 g in the morning and 0.5 g at night, po) [54]. Guo et al. reported a case of a patient with tuberculous meningoencephalitis who was also intolerant to LZD and switched to CZD (800 mg bid), on the bases of isoniazid, pyrazinamide, bedaquiline, moxifloxacin, and faropenem. In this case, steady-state concentrations of CZD in serum and CSF were determined at weeks 7 and 11 (7 h post-dose). The results showed that the serum concentrations were 9.64 mg/L and 9.36 mg/L, while the CSF levels measured 0.54 mg/L and 1.15 mg/L, respectively, which exceeded CZD’s M. tuberculosis MIC. The corresponding CSF-to-serum ratio at week 11 was 0.123, which approached the estimated 10% unbound serum fraction, indicating high free drug permeability into the CSF [55]. Recently, another case report documented the successful treatment of CZD (400 mg bid) combined with isoniazid and pyrazinamide for a patient with TBM and multiple comorbidities [56]. These cases provide a preliminary validation of the possible therapeutic potential of CZD in TBM.

The extant evidence from studies of CZD in other forms of EPTB is restricted to case reports. Kang et al. reported on a case of an 87-year-old female patient with tuberculous pleurisy, who suffered from thrombocytopenia due to the utilization of LZD (600 mg bid) as a component of her treatment regimen. After the patient switched to CZD (400 mg, q12h) in combination with cycloserine, the platelet count returned to normal, and the treatment for tuberculous pleurisy was continued for 4 weeks, resulting in a favorable outcome [57]. Liu et al. reported a case of a 54-year-old female patient who had undergone a chronic kidney allograft procedure and subsequently developed multisystem TB, including PTB, tuberculous pleurisy, and tuberculous peritonitis. The patient exhibited a high level of resistance to most first- and second-line anti-TB drugs, and after 2 weeks of LZD (600 mg qd), the patient developed severe myelosuppression. After the patient switched to a regimen containing CZD (400 mg, q12h), there was a restoration of normal body temperature, accompanied by a gradual reduction and subsequent resolution of ascites, which was complete by the third month of treatment. Routine blood tests returned to normal during the treatment period, with no adverse effects such as myelosuppression or neuropathy. She finally achieved good efficacy and safety results [58]. Zhou et al. presented a patient with PTB, TBM, and tuberculosis pleuritis, who was intolerant to the first-line treatment with secondary thrombocytopenia. After the patient discontinued thrombocytopenia-inducing drugs and was administered CZD for 2 weeks, the platelet count increased steadily, and the patient consented to undergoing long-term treatment with CZD [45].

Clinical Utility of CZD Against TB in Vulnerable Populations

Case reports have been published on the use of CZD to treat childhood TB in patients as young as 4 months old [59]. This 4-month-old male infant was born prematurely and developed pre-extensive DR-TB due to exposure from the mother. The LZD-containing regimen was suspected of leading to bone marrow suppression and lactic acidosis; thus, LZD was discontinued. Following confirmation of pre-extensive DR-TB, the treatment regimen was revised to include bedaquiline, delamanid, and CZD. During the 5-month follow-up period, negative TB culture conversion was achieved, pulmonary lesions were improved, and no significant adverse effects were reported. In another case report [60], a 4-year-old patient with tuberculous pleurisy and glucose-6-phosphate dehydrogenase deficiency experienced severe myelosuppression due to the treatment of other infections with LZD. Then, CZD was administered as a compassionate substitute for LZD concomitantly with other anti-TB drugs for more than 1 year. The patient exhibited a positive response to the treatment, and no AEs were observed. These findings suggest that CZD may be a potential and safe long-term therapeutic option for tuberculous pleurisy in children. A phase 2 trial (CTR20230232) is currently underway to assess the safety of CZD for pediatric therapy, and the results of subsequent studies will provide further confirmation of its dosages in children.

In addition, the efficacy and safety of CZD were demonstrated in an elderly patient with MDR-TB. The 90-year-old patient presented with multiple comorbidities, including hypertension, coronary artery disease, chronic kidney disease stage 3 (CKD-3), and prostate cancer, and had undergone pacemaker implantation 2 years ago. After being diagnosed with MDR-TB, the patient was treated with a CZD-containing anti-TB regimen. Subsequent long-term observation revealed that the patient demonstrated clinical improvement, characterized by significant absorption of pleural effusion and reduction of lung plaques/nodules. Pharmacokinetic analysis revealed steady-state concentrations of CZD: trough level of 1.27 μg/mL, and 2, 4, 6, and 10 h post-dose levels of 3.88, 6.32, 8.99, and 3.14 μg/mL, respectively [61]. This case provides a valuable clinical reference on the pharmacokinetic profile in elderly and renally impaired patients.

However, the aforementioned evidence of CZD against tuberculosis is limited to only one prospective clinical trial with small sample size, retrospective clinical studies, case reports, or case series. It is noteworthy that small sample sizes may lead to overestimation of the observed effects, while retrospective study designs are susceptible to selection bias. In addition, there may exist potential for publication bias, where positive results from small-scale studies are more likely to be published than negative findings. Nevertheless, several large-scale prospective clinical trials are currently underway, which will provide more robust and reliable evidence to validate the use of CZD as an anti-TB agent in the near future.