Successful treatment of pre-extensively drug-resistant tuberculous meningoencephalomyelitis in pregnancy with a bedaquiline and delamanid-based regimen: a case report

Abstract

Background

Management of pre-extensively drug-resistant tuberculosis (pre-XDR-TB) during pregnancy poses a formidable clinical challenge, particularly when complicated by tuberculous meningoencephalomyelitis (TBMEM), While the WHO operational handbook provides a general framework for drug-resistant TB, robust evidence and specific guidelines for managing severe CNS involvement in pregnancy remain limited.

Case presentation

We report the successful outcome for a mother and infant in an extremely high-risk case. The patient, at 17 + 6 weeks of gestation following in vitro fertilization (IVF), was diagnosed with pre-XDR-TB. Hematogenous dissemination was confirmed by chest CT showing diffuse miliary nodules, and spinal MRI confirmed meningoencephalomyelitis. Her clinical course was complicated by life-threatening conditions, including TB-associated sepsis (TB-Sepsis) and severe neurological immune reconstitution inflammatory syndrome (Neuro-IRIS) presenting as an intracranial hypertensive crisis. An individualized, multidisciplinary approach centered on a bedaquiline (Bdq) and delamanid (Dlm)-based regimen was implemented. The patient’s condition was effectively controlled, and she delivered a healthy female infant at 35 + 1 weeks of gestation. Both mother and infant recovered well.

Conclusions

This case demonstrates that a carefully monitored Bdq/Dlm-based regimen can be a life-saving option for severe DR-TB in pregnancy. It also underscores the critical need for systematic TB screening prior to assisted reproductive technology (ART) in high-burden regions.

Background

Managing drug-resistant tuberculosis (DR-TB) during pregnancy presents a significant clinical challenge, particularly for severe forms like pre-extensively drug-resistant tuberculous meningoencephalomyelitis (pre-XDR-TBMEM), where evidence for safe and effective treatment is scarce [1, 2]. The selection of anti-TB drugs is substantially complicated by concerns over potential teratogenicity, often leading to treatment delays or suboptimal regimens that jeopardize both maternal and fetal outcomes. The use of newer drugs, such as bedaquiline (Bdq) and delamanid (Dlm), has revolutionized DR-TB treatment. However, while the WHO Operational Handbook on Tuberculosis (2022 Update) provides guidance on using Bedaquiline and Delamanid during pregnancy [3], robust evidence and specific protocols for managing pre-XDR-TBMEM (involving the central nervous system) remain limited and largely rely on observational data [4, 5].

Here, we present an exceptionally complex case of a mid-trimester pregnant woman with pre-XDR-TBMEM, further complicated by TB-Sepsis and neurological immune reconstitution inflammatory syndrome (Neuro-IRIS). This report details the successful use of an individualized, Bdq/Dlm-based regimen within a multidisciplinary framework, which ultimately led to favorable outcomes for both mother and infant. It offers crucial insights into managing such critically ill patients, where the benefits of aggressive treatment must be weighed against potential fetal risks.

Case presentation

Patient Information: A 33-year-old female at 17 + 6 weeks of gestation (conceived via IVF-ET) was transferred to our hospital on September 26, 2024. Medical Profile: The patient had no history of HIV infection, diabetes mellitus, or autoimmune diseases. Her immunocompromised state was attributed to the physiological immune modulation of pregnancy. Past Medical History: She had a history of tuberculous pleurisy in 2018 (treated with 2HRZE/6HR but self-discontinued after 8 months without bacteriological confirmation) and recurrent pleurisy in 2020 (diagnosed clinically at a local hospital; treated with FDC-HRZE for one year). Crucially, as no pathogen was isolated, drug susceptibility testing (DST) could not be performed during these episodes.She underwent IVF-ET on June 12, 2024, due to fallopian tube blockage. Notably, despite her TB history, no specific TB screening (e.g., Chest X-ray or Interferon-Gamma Release Assay) was performed prior to IVF.

Clinical Findings & Diagnosis: On admission, vital signs showed tachycardia (127 bpm) but no hypotension. Neurological exam revealed nuchal rigidity and asymmetric limb weakness. Laboratory Findings (Reference ranges provided): Initial CSF analysis showed significantly elevated pressure > 330 mmH₂O (Ref: 70–200), nucleated cell count 340 × 10⁶/L (Ref: 0–5), glucose 0.75 mmol/L (Ref: 2.5–4.5), and protein 3147 mg/L (Ref: 150–450). Diagnostic Confirmation: On September 28, Targeted Next-Generation Sequencing (tNGS) (Platform: FASTASeq 300; Database: CARD v2.0.0) of the CSF confirmed Mycobacterium tuberculosis resistant to isoniazid, rifampicin, pyrazinamide, ethambutol, and fluoroquinolones. Diagnosis: The patient was diagnosed with pre-XDR-TB (defined as MDR/RR-TB with additional resistance to any fluoroquinolone, according to the WHO 2021 update). Culture Results: MGIT 960 liquid cultures for blood, sputum, and CSF were consistently negative, likely due to prior empirical anti-TB treatment received at the local hospital.

Treatment course (See Table 1 for detailed timeline)

Table 1.

Timeline of clinical events, diagnostic findings, and therapeutic interventions

Time (Days from Adm.)	Date	Key clinical events & diagnostics	Anti-TB regimen (Dosage & route)	Adjunctive therapy & management	Rationale for adjustment
Day 1	2024-09-26	Admission Severe headache, somnolence. ICP: >330 mmH₂O Dx: GeneXpert (+) for RR-TB	Empirical Regimen: Mfx (0.4 g qd), Lzd (600 mg qd), Mpm (1.0 g q8h)ᵃ, Am (0.6 g qd), H (0.6 g qd), Z (1.5 g qd)	Steroids: Dexamethasone 10 mg/d IV ICP Control: Mannitol 250 mL q6h	Empirical coverage for RR-TBM pending comprehensive DST.
Day 3	2024-09-28	Diagnosis Refined: Pre-XDR-TB tNGS: Resistant to H, R, Z, E + Fluoroquinolones. Culture: Negative (MGIT 960)ᵇ	Stop: Mfx, H, Z Start: Bdq (400 mg qd)ᶜ, Cs (250 mg am/500 mg pm)	Same as above.	Adjusted based on molecular DST showing FQ-resistance.
Day 6	2024-10-01	Adverse Event (CNS) Dizziness, sleep disturbance.	Stop: Cs Start: Dlm (100 mg bid)	Same as above.	Suspected Cs-related CNS toxicity; switched to Dlm.
Day 8	2024-10-03	TB-Sepsis & Organ Failure SOFA score: 5 ALT: 169→213 U/L; Cr: 146 µmol/L PCT: 0.31 ng/mL eGFR40.46 mL/min/1.73 m²	Hold: Bdq, Am (toxic) Continue: Dlm, Lzd, Mpmᵃ	ICU Transfer Stop Mannitol (renal risk); Switch to Glycerol-fructose. Liver protection therapy.	Sepsis-induced multi-organ dysfunction. Potentially hepatotoxic/nephrotoxic drugs withheld.
Day 13	2024-10-08	Stabilization Consciousness improved. Liver/Renal function recovering.	Continue: Dlm, Lzd, Mpmᵃ	Transferred out of ICU.	Clinical improvement.
Day 20	2024-10-15	Disease Extent Confirmed Chest CT: Miliary TB ICP: 250 mmH₂O	Restart: Bdq (200 mg tiw) Regimen: Bdq + Dlm + Lzd + Mpmᵃ	Add: Clopidogrel (for new lacunar infarction).	Liver function normalized; regimen re-intensified.
Day 29	2024-10-24	Symptom Fluctuation Intermittent fever, ICP 300 mmH₂O.	Restart: Cs (750 mg/d) Regimen: Bdq + Dlm + Lzd + Mpmᵃ + Cs	Increase Mannitol freq.	Intensification due to insufficient ICP control.
Day 35	2024-10-30	Neuro-IRIS Crisis ICP peak: 480 mmH₂O Worsening headache/fever.	Maintain: Full Regimen (Bdq + Dlm + Lzd + Mpmᵃ + Cs)	Aggressive IRIS Mgmt: Freq. Lumbar punctures + Intrathecal Dexamethasone (5 mg/dose).	Paradoxical reaction (IRIS) diagnosed. Regimen maintained; anti-inflammatory therapy escalated.
Day 43	2024-11-07	IRIS Controlled ICP decreasing, symptoms resolved.	Maintain: Full Regimen	Steroid Tapering: Switch to Oral Prednisone.	IRIS phase subsided.
Day 122	2025-01-25	Delivery 35 + 1 weeks gestation.	Maintain: Full Regimen	C-Section Infant: 1850 g, no TB infection.	Multidisciplinary decision for delivery.
Month 6	2025-03	Follow-up/Toxicity Hyperlactatemia (Lac 3.5 mmol/L).	Adjust Lzd: Reduced to 300 mg/d. Stop Mpm: Discontinued after 6 months.	Outcome: Mother: Full neuro-recovery. Infant: Healthy.	Lzd dose reduced due to mitochondrial toxicity; Mpm stopped after intensive phase.

Abbreviations: Adm: admission; ICP: intracranial pressure; RR-TB: rifampicin-resistant tuberculosis; tNGS: targeted next-generation sequencing; Mfx: moxifloxacin; Lzd: linezolid; Mpm: meropenem; Am: amikacin; H: isoniazid; Z: pyrazinamide; Bdq: bedaquiline; Cs: cycloserine; Dlm: delamanid

a. Meropenem Administration: Meropenem (1.0 g IV q8h) was administered in combination with oral Amoxicillin-Clavulanate (125 mg) given 30 min prior to each infusion to inhibit beta-lactamase degradation, as per carbapenem-containing TB regimens

b. Culture Results: MGIT 960 liquid cultures for blood, sputum, and CSF were consistently negative throughout the course, likely due to prior empirical anti-TB treatment received at the local hospital before transfer. Diagnosis and resistance profiling relied on GeneXpert and tNGS

c. Bedaquiline Dosing: Administered as a loading dose of 400 mg daily for the first 2 weeks, followed by 200 mg three times per week (tiw)

Phase 1: Induction & Adjustment (Day 1–7): Empirical therapy consisting of Mfx, Lzd, Mpm, Am, H, and Z was initiated on admission. Given the patient’s impaired consciousness (requiring nasogastric feeding) and the critical need for rapid bactericidal activity, an intravenous-based regimen was prioritized to ensure reliable bioavailability. This combination provided at least three effective agents (Lzd, Am, Mpm), as local epidemiological data in Hubei Province indicates extremely low resistance rates to these drugs. Although Bedaquiline (Bdq) is a core drug, it is currently only available in oral formulation. Therefore, its initiation was deferred pending the tNGS results (expected within 48 h) to confirm the resistance profile. On Day 3 (September 28), following the confirmation of FQ-resistance via tNGS, Mfx was immediately discontinued and replaced by Bdq to construct an effective pre-XDR regimen.

Phase 2: TB-Sepsis & ICU Care (Day 8–12): On October 3, the patient developed somnolence, tachypnea, and tachycardia. Laboratory results revealed multi-organ dysfunction: acute hepatic injury (ALT 169 U/L, AST 61 U/L; later peaking at 213 U/L and 130 U/L, respectively), renal impairment (BUN 12.74 mmol/L [Ref: 2.6–7.5], Cr 146 µmol/L [Ref: 41–73], and eGFR declined to 40.46 mL/min/1.73 m² [Ref: >90]), and myocardial injury (CK-MB max 28 U/L, LDH max 339 U/L). Coupled with elevated inflammatory markers (Procalcitonin 0.31 ng/mL; CRP 31.6 mg/L) and a SOFA score of 5, TB-Sepsis was diagnosed. The elevated PCT and CRP differentiated this systemic inflammatory response from pure drug-induced liver injury (DILI). Potentially toxic drugs (Bdq, Am) were withheld. She stabilized after 5 days in ICU.

Phase 3: Disease Extent Confirmation & Regimen Optimization (Day 18+): Bedaquiline was reintroduced on October 13 (Day 18). On October 15 (Day 20), a chest CT scan (performed following stabilization, as earlier transport was precluded by her critical instability) revealed diffuse miliary nodules in both lungs (Fig. 1A), confirming hematogenous dissemination.The anti-TB regimen was optimized to Bedaquiline (400 mg qd for 2 weeks, then 200 mg tiw), Delamanid (100 mg bid), Linezolid (600 mg qd), and Meropenem (1.0 g q8h). Meropenem was administered with oral Amoxicillin-Clavulanate to inhibit beta-lactamase.

Fig. 1.

Imaging evidence of disseminated tuberculosis and spinal involvement. (A) Chest CT scans (two representative slices) taken on October 15, 2024 (Day 20), showing diffuse miliary nodules distributed throughout both lungs (arrows), confirming hematogenous dissemination. (B) Contrast-enhanced MRI of the cervicothoracic junction (November 13, 2024) and (C) the lumbar spine (November 18, 2024), revealing linear meningeal enhancement along the spinal cord (arrows). These findings objectively support the diagnosis of tuberculous meningoencephalomyelitis

Phase 4: Neuro-IRIS Crisis (Day 35): On October 30, the patient developed severe headache and fever. ICP spiked to 480 mmH₂O. This was diagnosed as Neuro-IRIS. The anti-TB regimen was maintained. IRIS was managed with frequent CSF drainage and intrathecal dexamethasone injections (5 mg/dose). Spinal Involvement: Subsequent MRI of the spine (November 13 & 18) revealed linear meningeal enhancement along the cervical, thoracic, and lumbar spinal cord (Fig. 1B and C), objectively confirming the diagnosis of meningoencephalomyelitis.

Maternal and Infant Outcome: The patient underwent a cesarean section on January 25, 2025 (35 + 1 weeks). Neonate Assessment: The infant weighed 1,850 g. Placental pathology showed no evidence of granulomas or caseous necrosis. The neonate’s sputum culture (Day 1, 7) and T-SPOT.TB test (Day 1, 10) were negative. Follow-up: Serial brain MRI (Fig. 2) showed resolution of meningeal enhancement. The mother is scheduled for a total treatment duration of 18–20 months.

Fig. 2.

Serial Brain MRI scans demonstrating disease evolution. Columns represent time points: (A) October 15, 2024 (Initial assessment); (B) November 12, 2024 (During Neuro-IRIS crisis); (C) January 10, 2025 (Recovery). Note the extensive basal meningeal enhancement (white arrows) which paradoxically worsened in November (B) despite effective treatment, consistent with Neuro-IRIS, before resolving significantly in January (C)

Discussion and conclusions

This case highlights several critical management principles for extremely severe DR-TB in pregnancy. First, the successful navigation of two distinct life-threatening complications—TB-Sepsis and Neuro-IRIS—underscores the importance of dynamic clinical monitoring. The initial deterioration was attributed to TB-Sepsis, a severe systemic inflammatory response to a high bacillary load [6]. Crucially, this diagnosis was objectively supported by a SOFA score of 5 and significantly elevated procalcitonin (0.31 ng/mL), distinguishing it from drug toxicity, while diffuse miliary nodules on chest CT (Fig. 1A) confirmed hematogenous dissemination. In contrast, the later neurological worsening, occurring after initiation of effective therapy, was characteristic of paradoxical Neuro-IRIS, an aberrant immune response that required modulation with intensified corticosteroid therapy [7, 8]. Differentiating these two syndromes was crucial for tailoring appropriate management.

Second, this case provides vital real-world evidence supporting the use of a Bdq/Dlm-based regimen for life-threatening DR-TB during pregnancy. While safety data for these newer agents are still emerging, the WHO Operational Handbook (2022 Update) outlines their potential utility in MDR-TB regimens [3] and the maternal mortality risk of untreated pre-XDR-TBMEM is exceedingly high [5, 9]. Following extensive counseling and informed consent, a decision was made to prioritize maternal survival. Our experience aligns with recent findings suggesting that in severe cases, the benefits of Bdq-containing regimens likely outweigh the theoretical fetal risks, and good neonatal outcomes are achievable with close monitoring [4, 10, 11].

Finally, the patient’s history of recurrent TB and conception via IVF-ET without prior TB screening (specifically Chest X-ray or Interferon-Gamma Release Assay [IGRA]) highlights a significant gap in care. Genital TB is a known, often occult, cause of infertility (likely implicated in this patient’s tubal obstruction), and the immunological shifts during pregnancy can reactivate latent infection [12, 13]. This case argues strongly for incorporating systematic screening for both active and latent TB into pre-ART protocols, especially in high-burden settings.

In conclusion, this case demonstrates that with an individualized, multidisciplinary approach, it is possible to save both mother and infant in the face of pre-XDR-TBMEM with catastrophic complications during pregnancy. This provides an important reference for managing similar extreme cases and contributes crucial evidence for evolving global treatment guidelines.

Abbreviations

pre-XDR-TB

Pre-extensively drug-resistant tuberculosis

TBMEM

Tuberculous meningoencephalomyelitis

Bdq

Bedaquiline

Dlm

Delamanid

Neuro-IRIS

Neurological immune reconstitution inflammatory syndrome

DR-TB

Drug-resistant tuberculosis

IVF-ET

In-vitro fertilization and embryo transfer

CSF

Cerebrospinal fluid

RR-TB

Rifampicin-resistant tuberculosis

tNGS

Targeted next-generation sequencing

Cs

Cycloserine

SOFA

Sequential Organ Failure Assessment

ICU

Intensive Care Unit

ICP

Intracranial pressure

Author contributions

Q.N., Y.L. and F.X. contributed to the clinical management of the patient, data collection, and wrote the initial draft of the manuscript. Y.Z., T.F., L.Z., D.H., and Q.T. were involved in the multidisciplinary treatment and patient care. T.L. and L.T. conceived the study, supervised the project, and critically revised the manuscript. All authors have read and approved the final manuscript.

Funding

This work was supported by the Health Commission of Hubei Province Program (to Q.N.).

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study was approved by the Medical Ethics Committee of Wuhan Jinyintan Hospital (Approval No. Shen KY-2024-30.01). Written informed consent to participate was obtained from the patient.

Consent for publication

Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.

Competing interests

The authors declare no competing interests.