A 45-year-old Chinese male suffered with fever and in comatose was transferred to our hospital (The Third People's Hospital of Shenzhen) for specialist treatment on December 14, 2021 (day 1). His medical records showed that he had gradually aggravated headache, nausea, fatigue, and fever of a 38.5-39.0  C range for more than 2 weeks. He sought medical attention for his symptoms at a local clinic two weeks prior (December 1, 2021). His blood routine examination, rapid antigen test for type A/B flu virus, and routine urine examination were all normal. He was prescribed an empirical antibiotic therapy with Levofloxacin and Cefuroxime for five days. However, his fever, headache, and fatigue persisted, and his consciousness worsened. He is a smoker but does not consume alcohol. He has no history of chronic disease. He has no recent travelling history in the past 6 months. He was admitted to a local hospital and underwent a lumbar puncture (December 13, 2021). His CSF examination showed a prominent elevated protein level (2155 mg/dl; normal: 15-45 mg/dl) and a low glucose level (0.85 mmol/L; normal: 2.22-3.89 mmol/L). Chest CT showed nodules with calcification on the upper right lung, and consolidations in both lower lobes (Figure 1 A, B&C). Magnetic resonance imaging (MRI) showed ventriculomegaly, meningeal enhancement and hydrocephalus (Figure 2A-D). A diagnosis of TBM was highly suspected and he was transferred to our hospital. Upon admission, his physical examination showed body temperature of 37.1 C, pulse rate of 166 beats/min, breathing rate of 52 count/min, blood pressure of 159/119 mmHg, estimated body weight of 85 kg, and height of 180 cm. Neurological examination revealed confusion, neck stiffness, and positive Kernig sign with no motor, sensory, or cerebellar deficits. Laboratory findings in peripheral blood were as below: WBC 17.07x109/L, CRP 29.12 mg/L, ESR 59mm/h, normal electrolyte and normal liver and kidney function. Lumbar puncture was also performed at admission, which showed a CSF pressure of >330 mmH2O. CSF examination revealed WBC 375x106/L (reference: 0-8 x106/L), protein 2610 mg/dl (reference: 15-45 mg/dl), glucose 1.95 mmol/L (reference: 2.22-3.89 mmol/L). The simultaneous serum glucose level was 9.4 mmol/L. The patient was classified as grade 7 in the Glasgow Coma Scale (E2V2M3) and grade 4 in the Vellore grading system for tuberculous meningitis and hydrocephalus (TBMH). The patient underwent an emergency surgery of long-tunneled external ventricular drain (LTEVD) and Ommaya reservoir implantation under general anesthesia to relieve elevated intracranial pressure (Figure 3). GeneXpert MTB/RIF results of CSF were positive (semi-quantitative result: Medium) for TB-DNA with resistance to rifampicin. Antituberculosis treatment was commenced with isoniazid 800 mg/d, pyrazinamide 1500 mg/d, cycloserine 500 mg/d, moxifloxacin 400 mg/d, clofazimine 100 mg/d, and linezolid 600 mg twice a day. Dexamethasone 10mg per day was prescribed according to treatment guidelines. All the antituberculosis drugs and corticosteroids were administered while fasting. The patient's mental and athletic ability improved gradually. After ten days of treatment (December 23, 2021), we hypothesized that the drug concentration had reached a steady state. We monitored the drug concentration in his plasma and CSF before (at 0-hour) and after drugs administration (at 1-hour, 2-hour, 6-hour, and 12-hour) using High-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS, AB SCIEX 4500 Series of Instruments, Canada). Venous blood was collected and CSF was collected through LTEVD simultaneously. Pharmacokinetics of antituberculosis drugs in the plasma and CSF is shown in Figure 4. The CSF-to-plasma ratios, Cmax, Cmax/MIC in plasma and CSF were shown in Table S2. The maximum concentration of all anti-TB drugs met the expected concentration in plasma and in CSF except of moxifloxacin and clofazimine. As such, no adjustment was made to the dosage and composition of the antituberculosis regimen except that we lowered the dose of linezolid to 600 mg/d two weeks after treatment initiation and lowered the isoniazid dose to 600 mg/d.    
The LTVED was removed on January 03, 2022 (day 21). The patient was no longer bed-bound and started doing some step-by-step mobility activities. Whole-genome sequencing (WGS) of strain from CSF showed rpoB (S450L) and gyrA (D94G) mutation which confirmed that the isolate was resistant to both rifampin and fluoroquinolones. The diagnosis of pre-XDR-TBM was confirmed. Accordingly, moxifloxacin was removed from his regimen. Isoniazid was kept in the anti-TB regimen as WGS of our patient's CSF showed isoniazid susceptibility. The patient's condition gradually improved, and he was discharged after 36 days (January 19, 2022) in the hospital. He was in good status without any neurological sequelae. CSF phenotypic DST of Mycobacterium tuberculosis on day 45 further confirmed resistance to rifampin and fluoroquinolones. The Minimum inhibitory concentration (MIC) values for anti-TB drugs were determined except for linezolid and clofazimine (Table S1). After two months of antituberculosis therapy, brain MRI and CT scan showed a remissive state of ventriculomegaly, meningeal enhancement, and hydrocephalus (Figure 2E-H). Chest CT showed that his lung lesions improved (Figure 1D-F). Laboratory results of his CSF over the course of hospitalization are shown in Table 1. The timeline depicting major clinical events is shown in Figure 5. Throughout the whole anti-TB treatment phase, we monitored his hepatic function regularly and it turned out normal. As of press time, the patient's anti-TB treatment is still ongoing. He is in good physical condition with no disability. Anemia and peripheral neuritis were reported at the 6th month of anti-TB treatment and resolved after decreased dosage of linezolid to 600mg every other day and isoniazid to 300mg daily. He refused to do the therapeutic drug monitoring (TDM) so we could not get more details of his anti-TB drugs' concentration in plasma or CSF.