SUMMARY
SETTING:
National Center for Tuberculosis and Lung Diseases (NCTLD), Tbilisi, Georgia.
OBJECTIVE:
To determine clinical outcomes of patients with tuberculous meningitis (TBM) treated with an intensified regimen including a fluoroquinolone (FQ) and an injectable agent.
DESIGN:
Prospective cohort of patients aged 16 years initiating treatment for TBM at the NCTLD from January 2018 to December 2019. Treatment outcomes and neurologic disability at 1, 6 and 12 months after treatment initiation were assessed.
RESULTS:
Among 77 patients with median follow-up time of 363 days (IQR 269–374), 97% received a FQ, 62% an injectable agent, 44% linezolid and 39% a carbapenem. Fifty-seven patients (74%) successfully completed treatment, 2 (2.6%) had treatment failure, 6 (7.8%) died, and the remainder (12%) were lost to follow up. Among 11 patients treated for multidrug-resistant TBM, the median follow-up time was 467 days and one patient (8%) died. Regarding neurologic outcomes, 14/76 (18%) patients had Modified Rankin Scores of 0 at baseline, improving to 85% (56/66) and 94% (47/50) at 6 and 12 months, respectively.
CONCLUSION:
Intensified multidrug treatment regimens including a FQ and an injectable agent in all patients and newly implemented drugs in patients with multidrug-resistant TBM resulted in low mortality and favorable neurologic outcomes.
Keywords: multidrug-resistant, TBM, mortality, neurologic outcomes, empiric regimen, linezolid
RÉSUMÉ
CONTEXTE :
Centre national de lutte contre la TB et les maladies respiratoires (NCTLD), Tbilisi, Géorgie.
OBJECTIF :
Déterminer les résultats cliniques des patients atteints de méningite tuberculeuse (TBM) traitéis par schéma thérapeutique renforcé comprenant une fluoroquinolone (FQ) et un agent injectable.
SCHEMA :
Cohorte prospective de patients atteints de TBM âgés 16 ans mis sous traitement au NCTLD entre janvier 2018 et décembre 2019. Les résultats thérapeutiques et les séquelles neurologiques ont été évalués 1, 6 et 12 mois aprés l’instauration du traitement.
RÉSULTATS :
Parmi 77 patients dont la durée médiane du suivi était de 363 jours (IQR 269–374), 97% ont reçu une FQ, 62% un agent injectable, 44% du linézolide et 39% une carbapénème. Cinquante-sept patients (74%) ont mené à bien le traitement, deux (2,6%) ont connu un échec de traitement et six (7,8%) sont décédés. Les patients restants (12%) ont été perdus de vue. Parmi les 11 patients traités pour TBM multirésistante, la durée médiane du suivi était de 467 jours, et un patient (8%) est décédé. Quant aux résultats neurologiques, 14 (18%) des 76 patients avaient un score de Rankin modifié de 0 à l’inclusion, s’améliorant pour atteindre 85% (56/66) et 94% (47/50) à 6 et 9 mois de suivi, respectivement.
CONCLUSION :
Les schémas thérapeutiques renforcés à base de plusieurs médicaments contenant une FQ et un agent injectable chez tous les patients, et les nouveaux médicaments récemment utilisés chez les patients atteints de TBM multirésistante ont été associés à une faible létalité et à des résultats neurologiques favorables.
Tuberculous meningitis (TBM) is the most severe form of TBdisease, and more than half of those with drug-susceptible TBM experience severe disability or death.1 Outcomes in multidrug-resistant (MDR) TBM are even worse, with mortality rates estimated at 70%.2–4 There is an urgent need to develop new treatment strategies and to determine how outcomes in TBM can be improved.
The optimal combinations, durations, doses and frequencies of drug regimens for TBM have not been determined, and limited evidence is available to guide empiric treatment regimens for TBM.5 Not all first-line anti-TB agents penetrate the blood-brain barrier effectively: rifampin achieves cerebrospinal fluid (CSF) concentrations of ~10–20% of serum concentration,6 and ethambutol has CSF concentrations ~20–30% of serum.5 Second-line drugs with good CSF penetration include fluoroquinolones (FQs), ethionamide, cycloserine, and linezolid (LZD).4,5,7,8 Limited data are available on the use of novel and repurposed anti-TB agents, clofazimine, bedaquiline (BDQ), and delamanid (DLM) in MDR-TBM treatment.5
Given the historically poor clinical outcomes of drug-susceptible and MDR-TBM, how best to intensify TBM treatment regimens to improve outcomes is the subject of great interest in the international TB community.9 Improved outcomes with the use of an intensified treatment regimen (defined as the use of >5 likely effective drugs, including an FQ and an injectable agent) has been suggested for pulmonary MDR-TB.10 However, little is known about the impact of initiating a similarly intensified treatment regimen in TBM.
In 2015, the National TB Program (NTP) in the country of Georgia updated their TBM treatment guidelines to adopt an intensified regimen with a 2-month course of rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), an FQ and an injectable agent with the purpose of increasing the likelihood of adequate empirical antimicrobial coverage. This provided a unique opportunity to study the clinical outcomes of this intensified treatment regimen in a setting with high rates of drug-resistant TB.
STUDY POPULATION AND METHODS
Setting and participants
This prospective cohort study was carried out at the National Center for Tuberculosis and Lung Diseases (NCTLD) in Tbilisi, Georgia. The NCTLD campus contains the national TBM referral center which cares for approximately 70 patients per year. Patients aged 16 years treated in the NCTLD adult TBM ward from January 2018 to December 2019 were eligible for inclusion. Written informed consent was required from all study participants, and approval was obtained from the institutional review boards of Emory University, Atlanta, GA, USA, and the NCTLD, Tbilisi, Georgia. Clinical data were collected at baseline, 14 days, 1, 6 and 12 months, and patient follow-up appointments in NTP clinics. Patients received follow-up with cardiology, neurology, ophthalmology, and otolaryngology according to the known toxicities of their therapeutic regimen.
Laboratory
All patients suspected of having TBM underwent a lumbar puncture; acid-fast bacilli (AFB) staining, liquid and solid culture and Xpert® MTB/RIF assay (Cepheid, Sunnyvale, CA, USA)were performed on cerebrospinal fluid (CSF). For patients with positive AFB culture identified as Mycobacterium tuberculosis, phenotypic first- and second-line drug susceptibility testing (DST) were performed.11
Treatment
The Georgia NTP guidelines implemented in 2015 recommend patients with suspected drug-susceptible TBM initiate a 2-month intensive course of RIF, INH, PZA, an FQ (levofloxacin, moxifloxacin, or ofloxacin) and an injectable agent (amikacin, kanamycin, or capreomycin) and a 10–12 month course of RIF, INH, and/or levofloxacin. Regimens were individualized based on treatment history, comorbidities, and DST results. Weight-based dosing was implemented for most drugs as outlined in Supplementary Table 1. Among patients treated for MDR TBM, regimens were based on Xpert and DST results and recommend treatment duration was 18–20 months. All patients received a 6–8 week course of dexamethasone (400–1200mg). All patients with MDR-TBM received directly observed therapy (DOT). For drug-susceptible TBM, patients received a combination of observed and self-administered therapy (observed therapy 3 times per week for the first 2 months, then once per week).
Data management
Baseline characteristics were collected according to guidance from the TBM International Research Consortium.12 Diagnostic certainty was determined according to the Uniform TBM Research Case Definition Criteria.12,13 Treatment success was defined as completion of treatment (9 months for drug-susceptible and 18 months for MDR-TBM) and clinical improvement. Treatment failure was defined as lack of clinical improvement during a 6-month period or adverse reaction to therapy requiring cessation of treatment. For patients requiring >1 course of therapy, the final course was used to define treatment outcome. Modified Rankin Scale (MRS) scores of 0–5 and Glasgow Outcome Scale (GOS) scores of 1–15 were defined as previously reported to assess long-term functional outcomes.14,15 Duration of follow-up was defined as the time from admission at NCTLD until date of death, loss to follow-up, or final NCTLD database check on March 7th, 2021.
Statistical methods
Descriptive statistics were calculated for all participants. Missing data are presented as collected and were not imputed. Analyses were carried out using R software (R Computing, Vienna, Austria).16
RESULTS
Participants
Among 131 patients initiating treatment for TBM who were approached for enrollment, 78 patients consented to participate and 77 were included in final analysis (Figure 1). Among patients not enrolled, 21 patients were not selected during the pilot enrollment period, 29 declined participation, and 3 died before being approached for study participation. One patient was excluded from final analysis due to an alternate diagnosis of bacterial meningitis.
Figure 1.
Study flow diagram. *Alternative diagnosis: laboratory finding of positive Streptococcus culture without molecular or culture confirmation of M. tuberculosis, considered to be bacterial meningitis diagnosis.
Among the 77 patients with TBM included, the median age was 41.0 years, 40 patients (52%) were male, and 9 (12%) were co-infected with HIV. Among female participants, 6/37 (16%) were pregnant, <3 months post-partum, or had a recent spontaneous abortion at time of treatment initiation (Table 1). On clinical presentation, 76 patients (99%) reported headache, 74 (96%) each of fever and neck stiffness, 63 (82%) night sweats, and 53 (69%) weight loss (Table 1).
Table 1.
Baseline characteristics and diagnostic testing results
| (n = 77) n (%) |
|
|---|---|
| Baseline characteristics | |
| Male sex | 40 (52) |
| Age, years, median [IQR] | 41.0 [32.0–52.0] |
| Body mass index, median [IQR] | 24.2 [22.2–26.3] |
| Nationality | |
| Georgian | 68 (88) |
| Azerbaijani | 9 (12) |
| Time from outside hospital to NCTLD admission, days, median [IQR] | 6.0 [3.0–10.0] |
| HIV-positive | 9 (12) |
| Prior TB diagnosis | 13 (17) |
| Contact with known TB case | 9 (12) |
| Received BCG vaccine, self-reported | 72 (94) |
| Diabetes | 7 (9.1) |
| Positive hepatitis C virus antibody | 8 (10) |
| Inject on drug use | 5 (6.5) |
| Ongoing or recent pregnancy* (n=37) | 6 (16) |
| Symptoms at presentation | |
| Night sweats | 63 (82) |
| Fever | 74 (96) |
| Weight loss | 53 (69) |
| Cough >2 weeks | 18 (23) |
| Headache | 76 (99) |
| Seizures | 7 (9.1) |
| Cranial nerve palsy | 28 (36) |
| Neck stiffness | 74 (96) |
| Any clinical evidence of extraneural TB | 17 (22) |
| Diagnostic characteristics and multidrug resistance | |
| Diagnostic certainty | |
| Unlikely | 1 (1.3) |
| Possible | 54 (70) |
| Probable | 4 (5.2) |
| Confirmed in CSF | 18 (23) |
| TBM confirmed using Xpert or AFB culture | |
| Not confirmed | 54 (70) |
| Confirmed on CSF sample† | 18 (23) |
| Confirmed using extraneural sample only‡ | 5 (6.5) |
| Treatment category | |
| Susceptible | 66 (86) |
| MDR-TB defined clinically | 6 (7.8) |
| MDR-TB confirmed using culture§ | 5 (6.5) |
| Characteristics of clinically defined MDR-TB patients (n = 6) | |
| Had known MDR-TB contact | 3/6 (50) |
| Failed first course of TBM treatment | 3/6 (50) |
| Previously received TB treatment | 3/6 (50) |
| Drug susceptibility testing (Xpert and AFB culture) | |
| Rifampin resistance | 5/22 (23) |
| Isoniazid resistance | 5/18 (28) |
| Ethambutol resistance | 4/19 (21) |
| VDRL testing (syphilis) | |
| Negative | 31 (40) |
| Not done | 37 (48) |
| Bacterial culture results¶ | |
| Positive | 2 (3) |
| Negative | 23 (30) |
| Not done | 52 (68) |
| Diagnostic imaging | |
| Received any imaging (MRI brain, CT head or MRI spine) | 70 (91) |
| CT head performed | 40 (52) |
| MRI brain performed | 35 (45) |
| Any abnormal neurologic imaging | 34 (44) |
| CSF testing | |
| WBC count, cells/μL, median [IQR] | 166 [97–288] |
| Lymphocyte, %, median [IQR] | 85 [76–92] |
| Neutrophil,% , median [IQR] | 5 [3–11] |
| Total protein, mg/dL, median [IQR] | 99 [66–165] |
| CSF glucose, mg/dL(normal: 45–80 mg/dL), median [IQR] | 47 [29–65] |
| CSF with 10–500 cells/μL (normal: < 5 cells/μL) | 68/74 (92) |
Includes women who were pregnant at start of treatment (n = 1), women who were <3 months peripartum at treatment initiation (n = 3), and women who experienced a spontaneous abortion within 6 weeks of treatment initiation (n = 2).
One CSF sample was derived from spinal surgery; the rest were from diagnostic lumbar punctures.
Three sputum samples yielded positive molecular (Xpert) test results, one lymph node biopsy yielded both positive molecular testing and M. tuberculosis culture. Another lymph node biopsy and one tissue sample from an orchiectomy yielded positive M. tuberculosis cultures.
Among patients with MDR-TB confirmed using diagnostic susceptibility testing, one patient had pre-XDR-TB and the rest had MDR-TB; none of these 6 patients had confirmed XDR-TB.
Positive bacterial cultures: one patient with Staphylococcus aureus growth and M. tuberculosis confirmed by lumbar puncture. One patient with Streptococcus growth, without molecular or culture confirmation of M. tuberculosis, who had been previously treated for TB at NCTLD. All bacterial cultures performed at other hospitals.
IQR = interquartile range; NCTLD = National Center for Tuberculosis and Lung Diseases; BCG = bacille Calmette-Guérin, CSF = cerebrospinal fluid; TBM = tuberculous meningitis; AFB = acid-fast bacilli; MDR-TB = multidrug-resistant TB; VDRL = Venereal Disease Research Laboratory; MRI = magnetic resonance imaging; CT = computed tomography; WBC = white blood cell; XDR-TB = extensively drug-resistant TB.
Diagnosis
All patients received a lumbar puncture. On diagnostic testing, 23/77 (30%) patients had confirmed M. tuberculosis on Xpert or positive AFB culture. Of these, 18 (23%) patients met the Uniform TB Meningitis Research Case Definition Criteria for confirmed M. tuberculoshs in a CSF sample, and 5 patients (6.5%) had M. tuberculosis confirmed in a non-CSF sample (Table 1). Patients without CSF confirmation of M. tuberculoshs were treated for TBM based on CSF profiles at presentation and clinical judgment. The mean CSF WBC count was 166 cells/μL (interquartile range [IQR] 97–288) with a median of 85% lymphocytes (IQR 76–92) and 5% neutrophils (IQR 3–11) (Table 1).
Eleven (14%) of 77 patients in the cohort were considered to have MDR-TBM; five patients had MDR confirmed using DST and 6 were given a clinical diagnosis of MDR (Table 1). Among the 6 patients with clinically defined MDR, 3 were initially treated for drug-susceptible TBM and re-categorized following failure of first treatment (lack of clinical improvement). The remaining three MDR patients were defined by a contact with known MDR TB.
Treatment
As part of the initial treatment regimen, 72/77 (93%) patients received RIF, 74 (96%) INH, 55 (71%) PZA, 75 (97%) an FQ, 47 (61%) an injectable agent, 29 (38%) LZD, and 34% a carbapenem (meropenem or imipenem) (Table 2). Throughout the course of treatment, 48 patients (62%) received an injectable agent, 34 (44%) received LZD, and 39% received a carbapenem (Table 2). Among 11 patients treated for MDR-TBM, 8 (73%) received an injectable agent, 10 (91%) LZD, and 7 (64%) a carbapenem during treatment. Patients with MDR-TBM were also frequently treated with novel and repurposed anti-TBM agents: 9 (82%) received clofazimine, 6 (55%) received DLM, and 4 (36%) received BDQ (2 received both DLM and BDQ).
Table 2.
Drug regimens, dosing and duration of therapy
| Drug | Inclusion in drug regimens | Dosing (starting dose, all drug regimens) (mg) Mode (min, max) |
Duration of therapy (days) Median [IQR] |
|
|---|---|---|---|---|
| Initial regimen* n (%) |
Ever in regimen n (%) |
|||
| Isoniazid | 74 (96.1) | 75 (97.4) | 300 (300, 600) | 337 [164–366] |
| Rifampin | 72 (93.5) | 73 (94.8) | 600 (450, 600) | 341 [149–366] |
| Pyrazinamide | 55 (71.4) | 57 (74) | 1600 (800, 1600) | 61.5 [17–195] |
| Ethambutol | 49 (63.6) | 58 (75.3) | 1200 (400, 1200) | 81.5 [42–301] |
| Any fluoroquinolone | 75 (97.4) | 75 (97.4) | ||
| Ofloxacin | 48 (62.3) | 49 (63.6) | 800 (400, 800) | 14 [8–18] |
| Levofloxacin | 37 (48.1) | 66 (85.7) | 750 (250, 1000) | 93.5 [31–346] |
| Moxifloxacin | 23 (29.9) | 41 (53.2) | 400 (400, 400) | 26 [14–97] |
| Any injectable agent | 47 (61) | 48 (62.3) | ||
| Amikacin | 44 (57.1) | 45 (58.4) | 1000 (1000, 1000) | 17 [13–21] |
| Kanamycin | 12 (15.6) | 34 (44.2) | 1000 (750, 1000) | 38.5 [18–50] |
| Capreomycin | 4 (5.2) | 6 (7.8) | 1000 (1000, 1000) | 93 [61–128] |
| Any carbapenem | 26 (33.8) | 30 (39) | ||
| Imipenem | 20 (26) | 28 (36.4) | 2000 (1000, 2000) | 51.5 [31.5–68] |
| Meropenem | 9 (11.7) | 11 (14.3) | 2000 (1000, 2000) | 26 [10.5–46] |
| Linezolid | 29 (37.7) | 34 (44.2) | 600 (300, 600) | 69 [38–107] |
| Amoxicillin/clavulanic acid | 23 (29.9) | 29 (37.7) | 1000 (1000, 2000) | 52 [34–76] |
| Cycloserine | 6 (7.8) | 16 (20.8) | 750 (500, 750) | 92 [21–396] |
| Prednisone | 6 (7.8) | 7 (9.1) | 30 (15, 30) | 57 [25–118.5] |
| Delamanid | 2 (2.6) | 6 (7.8) | 200 (200, 2000) | 220 [135–303] |
| Prothionamide | 2 (2.6) | 3 (3.9) | 750 (500, 750) | 63 [40–322] |
| Bedaquiline | 1 (1.3) | 4 (5.2) | 400 (200, 400) | 473 [361–516] |
| Clofazimine | 1 (1.3) | 9 (11.7) | 100 (100, 200) | 371.5 [249–542] |
| PAS | 1 (1.3) | 1 (1.3) | 8000 (8000, 8000) | 86 [86–86] |
| Dexamethasone | 76 (98.7) | 76 (98.7) | 8 (4, 12) | 42.5 [31–64] |
Defined as initiation of therapeutic agent within 14 days of adimission to NCTLD.
IQR = interquartile range; PAS = para-aminosalicylic acid; NCTLD = National Center for Tuberculosis and Lung Diseases.
The median length of treatment for drug-susceptible TBM patients was 361 days (IQR 268–367) and median treatment length for MDR patients was 486 days (IQR 459–577). Additional information on the multidrug regimens is shown in Supplementary Tables S2 and S3 and Supplementary Figures S1–S4. In total there were 47 unique treatment regimens used (Supplementary Table S3), and five patients required >1 treatment course. No patients received surgical shunthng for hydrocephalus.
Outcomes
Among 77 patients with TBM, 57 (74%) patients had a favorable outcome, 3 (4 %) remained on treatment at completion of the study period (median treatment time 685 days, IQR 625–687), and the remaining patients had unfavorable outcomes)including loss to follow-up (9 patients, 12%), death (6 patients, 7.8%), and treatment failure (2 patients, 2.6%). Among all study participants, the median follow-up time was 363 days (IQR 269–374) (Table 3).
Table 3.
Final outcomes, overall and by drug resistance
| Final outcome | Overall (n = 77) n (%) |
Drug-susceptible (n = 66) n (%) |
MDR-TBM (n = 11) n (%) |
|---|---|---|---|
| Completed | 57 (74) | 51 (77) | 6 (55) |
| Lost to follow-up | 9 (12) | 9 (14) | 0 |
| Failure | 2 (3) | 1 (2) | 1 (9) |
| Death | 6 (8) | 5 (8) | 1 (9) |
| Still on treatment | 3 (4) | 0 | 3 (27) |
| Follow-up period, days, median [IQR] | 363 [269–374] | 360 [268–368] | 467 [424–562] |
MDQ = multidrug-resistant; TBM = tuberculous meningitis; IQR = interquartile range.
Of 11 patients treated for MDR-TBM, 6 (36%) successfully completed treatment, 3 (45%) remained on treatment at end of the study duration (median treatment length of 486 days), and 2 (18%) had unfavorable treatment outcomes (1 treatment failure and 1 death); overall mortality in the MDR group was 9% (1 of 11 patients with MDR-TBM). The median follow-up time among MDR-TBM patients was 467 days (IQR 424–562) (Table 3).
Throughout treatment, 51 adverse events were reported for 38 patients. Of these 25 (49%) were serious, 29 (57%) were related to TBM, and 17 (33%) were related to anti-TB treatment (Table 4).The most commonly reported adverse events were elevated liver enzymes and focal neurologic deficits. Two patients developed prolonged QTc and none developed hyponatremia. Among all adverse events, 35 (67%) resolved, 12 (24%) were ongoing at completion of the study period, and 5 (10%) resulted in death (Table 4).
Table 4.
Characteristics of adverse events reported during treatment and monitoring
| Adverse events (involved 38 patients) | (n = 51) n (%) |
|---|---|
| Characteristics | |
| Grade of adverse event | |
| Grade 1 or 2* | 23 (45) |
| Grade 3 or 4† | 28 (55) |
| Serious adverse event | 25 (49) |
| Related to TBM? | |
| Not related | 29 (57) |
| Possibly related | 13 (25) |
| Related | 9 (18) |
| Related to anti-TB treatment? | |
| Not related | 17 (33) |
| Possibly related | 28 (55) |
| Related | 6 (12) |
| Related to antiretroviral therapy? | |
| Not related | 44 (86) |
| Possibly related | 6 (12) |
| Related | 1 (2.0) |
| Outcome of adverse event | |
| Patient recovered | 34 (67) |
| Condition on-going at end of study | 12 (24) |
| Patient died | 5 (9.8) |
| Types of adverse events | |
| Worsening level of consciousness | 7 (14) |
| Focal neurologic deficit | 13 (25) |
| Hypokalemia | 5 (9.8) |
| Hyponatremia | 0 |
| Elevated AST/ALT | 14 (27) |
| QTc prolongation | 2 (3.9) |
| IRIS | 1 (2.0) |
| Elevated bilirubin | 5 (9.8) |
| Elevated creatinine | 2 (3.9) |
| Other | 44 (86) |
Asymptomatic, mild, minimal; local or noninvasive intervention indicated.
Requiring or prolonging hospitalization or life threatening.
TBM = tuberculous meningitis; AST = aspartate transaminase; ALT = alanine transaminase; IRIS = immune reconstitution inflammatory syndrome.
Neurologic outcomes for patients with TBM were assessed using MRS and GOS scores at 1, 6 and 12 months after treatment initiation (Figure 2). At 1 month, 14/76 (18%)patients reported a MRS score of 0, and the proportion of patients with MRS of 0 increased to 56/66 (85%) and 47/50 (94%) at 6 and 12 months after treatment initiation, respectively. At one month, 28/77 (36%) patients had low disability on GOS, and the proportion with low disability increased to 57/71 (80 %) and 48/56 (86%) at 6 and 12 months. Among 9 patients lost to follow-up, the median duration of follow-up was 66 days (IQR 49–149), and 5/9 patients lost to follow-up had a last reported MRS score of 0 or 1.
Figure 2.
Neurologic disability over the 12-month follow-up period. GOS and MRS scores were recorded at Month 1, 6 and 12 post-treatment. Note: Patients who died in the follow-up interval were included in follow-up GOS data, with GOS=1 as outcome, and were not included in follow-up MRS scores. GOS Scores: 1 = death; 2 = persistent vegetative state; 3 = severe disability; 4 = moderate disability; 5 = low disability. MRS Scores: 0 = I have no problems; 1 = I have some small problems, but have a normal lifestyle; 2 = I have some problems that interfere with my lifestyle, but I can take care of myself; 3 = I have some problems that interfere with my lifestyle and prevent independent living; 4 = I have problems that clearly prevent independent living, but do not need constant care; 5 = I have problems that make me totally dependent on others and need care day and night. GOS = Glasgow Outcomes Scale; MRS = Modified Rankin Scale.
DISCUSSION
Our prospective observational cohort study found high rates of favorable outcomes and a low mortality rate among patients with drug-susceptible and MDR-TBM treated with intensified multidrug treatment regimens as compared to historical controls.17 These results suggest that empiric administration of intensified multi drug treatment regimens may be beneficial in the treatment of TBM.
The relatively low mortality and neurologic disability in our cohort compare favorably with prior studies: recent meta-analyses have determined overall mortality rates of 22–25% among TBM cohorts.1,18,19 In prior MDR-TBM cohorts, mortality rates exceed 90% and drug resistance is strongly predictive of mortality. Recent data from the country of Georgia found a 24% mortality rate in patients with drug-susceptible TBM and a 67% mortality rate among patients treated for MDR-TBM; in this cohort, the majority of TBM patients received FQs and injectable agents, but only 4% of patients received LZD.17 Increased use of drugs that penetrate well into the CSF, including LZD, may be one reason for our favorable outcomes) given the concern for limited CSF penetration of first-line anti-TB agents.
Strengths of this study include a well-characterized prospective cohort with prolonged follow-up. The study adds important data to characterize clinical outcomes in TBM with the use of intensified treatment regimens in the setting of high rates of drug resistance; our findings support the role of a future clinical trial to determine whether early empiric administration of intensified multidrug treatment regimens is beneficial in TBM.
One notable characteristic of treatment regimens in this study was the relatively high rate of LZD, carbapenem, clofazimine, BDQ and DLM use. LZD achieves high CSF penetration with CSF concentrations achieving ~70% of serum levels,20,21 may be beneficial in improving neurologic outcomes of severe TBM)8,22 and is well-tolerated with a low rate of cytopenias.23 There are currently two ongoing controlled trials on LZD in TBM (NCT04021121 and NCT04145258). Scarce data are available on the CSF penetration of other novel and re-purposed anti-TB therapeutic agents. Meropenem achieves CSF concentrations of ~10% of serum,24 but has very high serum drug levels with intravenous administration; thus, it is uncertain whether meropenem and other carbape-nems achieve CSF concentrations above the minimum inhibitory concentration (MIC) for M. tuberculosis. Available data indicate DLM and BDQ have low total CSF concentrations,25,26 although total CSF concentrations are likely to underestimate the free CSF:plasma drug ratios, given that both drugs exhibit high protein binding in plasma. Further data are needed to understand how well novel and re-purposed anti-TB drugs penetrate the CSF and to determine the efficacy and optimal regimens of these drugs.
One unexpected finding in our prospective cohort was a higher rate of current or recent pregnancy among women with TBM than would be expected by chance. Prior studies have found increased risk of TB among post-partum women thought to be attributable to increased risk of TB disease during pregnancy and diagnostic delays.27,28 However, to our knowledge an association between pregnancy and TBM has not been shown. Our observational findings raise the question of whether biologic changes in pregnancy, including altered tryptophan catabolism in placental tissue29,30 and suppression of the T-helper proinflammatory response,31 may increase the risk of developing active TB disease and progression to TBM.
Additional findings from our study can be used to tailor treatment regimens in TBM. There were 47 unique treatment regimens among 77 patients, demonstrating the breadth of treatment options available and the importance of individualizing therapeutic regimens for TBM.
Our study is subject to several limitations. This was an observational study with no comparator group; we therefore used historical controls. Furthermore, some patients in our cohort remained in treatment at the completion of the study period. Despite intensive follow-up protocols, we experienced some loss to follow-up (12%) and were missing 6- and 12-month neurologic outcomes in 8% and 27% of participants, respectively. However, we achieved a prolonged follow-up period among the majority of the cohort (median follow-up 363 days).
CONCLUSION
Intensified multidrug treatment regimens that included an FQ, an injectable agent and frequent LZD and carbapenem use resulted in a low mortality rate and favorable neurologic outcomes in this cohort of patients with TBM compared to historical controls. Empiric administration of intensified multidrug therapy may be beneficial for TBM, particularly in settings with high rates of drug resistance. Our findings support the need for randomized controlled trials to assess the efficacy of intensified multidrug therapy in TBM.
Supplementary Material
Acknowledgements
The authors thank the physicians, nurses, and staff at the NCTLD in Tbilisi, Georgia, who provided care for the patients with TBM in this study. This work was supported by grants from the National Institutes of Health (NIH) and National Institute of Allergy and Infectious Diseases [5R03AI139871-02]; NIH Fogarty International Center [D43TW007124]; and NIH National Center for Advancing Translational Science [TL1TR002382 and UL1TR002378], Bethesda, MD, USA.
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