Expert Review of Anti-infective Therapy

ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: https://www.tandfonline.com/loi/ierz20

Management of complex tuberculosis cases: a

focus on drug-resistant tuberculous meningitis

Ravindra Kumar Garg, Imran Rizvi, Hardeep Singh Malhotra, Ravi Uniyal &
Neeraj Kumar

To cite this article: Ravindra Kumar Garg, Imran Rizvi, Hardeep Singh Malhotra, Ravi Uniyal
& Neeraj Kumar (2018) Management of complex tuberculosis cases: a focus on drug-
resistant tuberculous meningitis, Expert Review of Anti-infective Therapy, 16:11, 813-831, DOI:
10.1080/14787210.2018.1540930

To link to this article: https://doi.org/10.1080/14787210.2018.1540930

Published online: 07 Nov 2018.

Submit your article to this journal

Article views: 428

View related articles

View Crossmark data

Citing articles: 1 View citing articles

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ierz20
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY
2018, VOL. 16, NO. 11, 813–831
https://doi.org/10.1080/14787210.2018.1540930

REVIEW

Management of complex tuberculosis cases: a focus on drug-resistant tuberculous

meningitis
Ravindra Kumar Garg, Imran Rizvi, Hardeep Singh Malhotra, Ravi Uniyal and Neeraj Kumar
Department of Neurology, King George Medical University, Lucknow, India

ABSTRACT ARTICLE HISTORY

Introduction: Drug-resistant tuberculous meningitis has been reported worldwide. Isoniazid mono- Received 5 February 2018
resistance is the most frequent cause of drug-resistant tuberculous meningitis, a life-threatening Accepted 12 October 2018
disease. Extensive drug-resistant tuberculous meningitis has also been reported in some isolated case KEYWORDS
reports. Multidrug-resistant
Areas covered: We reviewed the current literature on drug-resistant tuberculous meningitis, as well as tuberculosis; Mycobacterium
drug-resistant tuberculosis. tuberculosis; CNS
Expert commentary: Drug-resistant tuberculous meningitis is a life-threatening disease and needs tuberculosis; miliary
prompt diagnosis and treatment. Xpert MTB/RIF Ultra technology can detect Mycobacterium tuberculosis tuberculosis; disseminated
and rifampicin resistance in cerebrospinal fluid (CSF) even with low numbers of bacilli. The optimum tuberculosis
antituberculosis drug regimen for multidrug-resistant tuberculous meningitis is largely unknown as no
second-line antituberculosis drug-containing regimen has been tested in a randomized controlled
fashion in drug-resistant tuberculous meningitis. A combination of levofloxacin, kanamycin, ethiona-
mide, linezolid, and pyrazinamide would be an appropriate regimen because of excellent CSF profile of
most of these drugs. End TB Strategy will help in checking the increasing challenge of drug-resistant
tuberculous meningitis as it aims to eliminate all kinds of tuberculosis by the year 2035.

1. Introduction tuberculosis, drug-resistant tuberculous meningitis, multi-

drug-resistant tuberculous meningitis, and drug-resistant CNS
Multidrug-resistant tuberculosis is caused by a strain of
tuberculosis. In case information on drug-resistant tuberculous
Mycobacterium tuberculosis that is resistant to at least isoniazid
meningitis was not available, that of drug-resistant pulmonary
and rifampicin. Extensively drug-resistant tuberculosis is resis-
tuberculosis was extrapolated. Physicians treating drug-resis-
tant to any fluoroquinolone, and at least one of three inject-
tant tuberculous meningitis often need to extrapolate from
able second-line drugs (amikacin, kanamycin, or capreomycin)
the recommendations made for the treatment of drug-resis-
along with isoniazid and rifampicin. Isolated resistance to one
tant pulmonary tuberculosis.
first-line antituberculosis drug is known as mono-resistance [1]
(Table 1). Rifampicin resistance is considered a surrogate mar-
ker for isoniazid resistance and multidrug-resistant tuberculo- 2. Epidemiology
sis. Primary drug resistance refers to a drug-resistant M.
Tuberculosis is amongst the 10 leading causes of death world-
tuberculosis strain infection in a previously untreated patient.
wide. In 2016, 10.4 million people had tuberculosis, and
The primary drug-resistant and susceptible strains get trans-
approximately 1.7 million died as a result. According to recent
mitted the same way. Acquired drug resistance is the result of
World Health Organization (WHO) data, there were approxi-
inadequate, incomplete, or poor treatment that allows the
mately 490,000 new cases of multidrug-resistant tuberculosis
selection of mutant-resistant M. tuberculosis strains [1].
in 2016, with 6% of them extensively drug-resistant. India,
Drug-resistant tuberculous meningitis is characterized by
China, and the Russian Federation collectively bear approxi-
resistant M. tuberculosis isolates that are recovered from either
mately 50% of the global burden of multidrug-resistant tuber-
the cerebrospinal fluid (CSF) or extra central nervous system
culosis [2].
(CNS) sites like lymph nodes and lungs, in patients with prob-
Drug-resistant tuberculous meningitis cases have been
able tuberculous meningitis. We comprehensively reviewed
reported from all over the world. Majority of these reports
existing literature on drug-resistant tuberculous meningitis,
are from high tuberculosis burden countries, mainly India,
concerning current knowledge on the epidemiology, patho-
Indonesia, China, Philippines, Pakistan, Nigeria, and South
genesis, diagnosis, treatment, and prevention of this disease.
Africa. Isoniazid mono-resistance is the most frequent form
Data from all the age groups of patients were analyzed.
of drug-resistant tuberculous meningitis, although multidrug-
PubMed, Scopus, and Google Scholar databases were
resistant cases have also been reported across the globe. A
searched using the following key words: drug-resistant
recent study from the USA reported that approximately one-

CONTACT Ravindra Kumar Garg garg50@yahoo.com Department of Neurology, King George Medical University, Lucknow, Uttar Pradesh 226003, India
© 2018 Informa UK Limited, trading as Taylor & Francis Group
814 R. K. GARG ET AL.
Table 1. Definitions of various drug resistance patterns [1].
Type of resistance Definitions
Mono-resistance Resistance to one first-line antituberculosis drug
only
Poly-resistance Resistance to two or more first-line drugs but not to
both isoniazid and rifampicin
Multidrug resistance Resistance to at least both isoniazid and rifampicin
(MDR)
Extensive drug Resistance to any fluoroquinolone and at least one
resistance (XDR) of three second-line injectable drugs along with
multidrug resistance
Rifampicin resistance Rifampicin resistance, with or without resistance to
(RR) other antituberculosis drugs
fifth (61/324) of tuberculous meningitis cases were caused by
multidrug-resistant strains. Additional 6 isolates had rifampicin
mono-resistance, and 32 (10%) isolates had isoniazid mono-
resistance [3]. In China, CSF isolates from approximately 48%
(12/25) of the tuberculous meningitis cases demonstrated
phenotypic drug resistance. Beijing strain was the most com-
mon genotype encountered, and 45% (9/20) of the cases
demonstrated drug resistance [4]. The incidence of drug-resis-
tant tuberculous meningitis is much less in India, with approxi-
mately 8% (n = 14) and 3% (n = 6) of CSF isolates showing
isoniazid mono-resistance and multidrug-resistance, respec-
tively. In this study, drug susceptibility testing was done in
191 isolates and in 77% of cases, isolates were sensitive to all
first-line antituberculosis drugs. Data from Vietnam has also
demonstrated a similar rate of M. tuberculosis drug-resistance
among tuberculous meningitis cases [5,6]. In the developed
countries, drug-resistant tuberculous meningitis is frequent
among the immigrants [7]. Surprisingly, no reports are avail-
able regarding drug-resistant tuberculous meningitis in
Russian Federation, which harbors the highest incidences of
multidrug-resistant tuberculosis. The proportion of patients
suffering from drug-resistant tuberculous meningitis, across
various studies, has been listed in Table 2. In a few isolated
cases, extensively drug-resistant M. tuberculosis strains caused
meningitis (Table 3).
3. Pathogenesis and pathology
Classically, pathogenesis of tuberculous meningitis is consid-
ered to be a two-stage process. M. tuberculosis is transmitted
via airborne droplet nuclei mechanism. A tubercular focus
then develops in the lung, which subsequently releases the
bacteria into the bloodstream. It reaches the brain via the
hematogenous route, where it is deposited as small granulo-
mas in the meninges and subpial brain parenchyma (Rich
focus). Tuberculous meningitis develops when a caseating
Rich focus releases caseous material containing M. tuberculosis
into the subarachnoid space [36]. Donald and co-workers,
alternatively, suggested that meningeal or subcortical tuber-
culous focus, in children with miliary tuberculosis, develops
during the process of miliary dissemination. These tuberculous
foci soon after its development may caseate and discharge its
contents into the subarachnoid space causing meningitis [37].
In a zebrafish model, it was demonstrated that
Mycobacterium tuberculosis bacilli use macrophages as Trojan
horse to cross the blood–brain barrier and invade CNS [38].
The hallmark pathologic features are meningeal inflammation
and collection of basal thick gelatinous exudates. Arteries of
the circle of Willis passing through these basilar exudates get
strangulated with resultant inflammatory changes in the cere-
bral vessel wall. Occlusion of the involved arteries produces
brain infarcts in the corresponding perfusion zones. Optic,
abducens, and oculomotor nerves are the most frequently
affected cranial nerves. Hydrocephalus is almost an inevitable
complication of tuberculous meningitis. Thick exudates block
the CSF flow. Hydrocephalus is either of communicating type
or obstructive type. Communicating hydrocephalus is recog-
nized, on neuroimaging, by a dilated fourth ventricle while the
fourth ventricle remains unaffected in obstructive hydroce-
phalus. Cerebral tuberculomas are either present early in the
course of disease or paradoxically develop during the treat-
ment phase. Tuberculomas consist of caseous necrotic tissue,
epithelioid cell granuloma, and mononuclear cell infiltration.
Exudates also encase the lower part of the spinal cord and
cauda equina resulting in tuberculous radiculomyelopathy
[39,40].
4. Extra CNS involvement
Extra-CNS involvement is frequently observed in meningeal tuber-
culosis. Lung and lymph node involvement is common either as a
part of miliary or disseminated tuberculosis [41](Table 3). The latter
is characterized by the presence of M. tuberculosis in two or more
noncontiguous body parts [42]. Miliary tuberculosis, on the other
hand, is characterized by the presence of diffuse miliary infiltrates
in chest radiograph or high-resolution computed tomography (CT)
or miliary tubercles in multiple organs. Abnormalities in chest
radiographs (10/33) and abnormal thorax CT (15/22) are common
in tuberculous meningitis [43]. Thoracic imaging of patients has
shown various pulmonary lesions like cavitation, mediastinal or
hilar lymphadenopathy, pulmonary nodularity, consolidation,
pleural effusions, and tuberculous spondylodiscitis [44]. Invasive
respiratory sampling consisting of bronchoscopy with bronchoal-
veolar lavage yields a higher number of microbiologically con-
firmed tuberculous meningitis cases. Thus, the workup should
include thorax CT, bronchoscopy, and bronchoalveolar lavage [45].
5. Clinical features
The classical clinical manifestations of tuberculous meningitis
are fever, headache, vomiting, altered sensorium, and nuchal
rigidity. The duration of illness before symptomatic presenta-
tion is usually greater than 5 days [46]. Cranial nerve palsies,
vision loss, focal neurological deficits, and signs of raised
intracranial pressure are common in advanced stages. The
sixth cranial nerve is the most commonly affected cranial
nerve in tuberculous meningitis [47]. Optic nerve involve-
ment is often seen, leading to profound vision loss either
caused by optochiasmatic arachnoiditis, large hydrocephalus,
optic nerve granuloma, or ethambutol toxicity [48]. Infarcts,
leading to focal neurological deficits, are also common.
Infarcts are classically located at the internal capsule, basal
ganglion, and thalamic regions [49]. Paraplegia is caused by
tuberculous radiculo-myelitis and spinal cord tuberculoma. In
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 815

Box 1. Case Vignette

A 32-year-old lady with complaints of fever and headache from 2-months, presented in a state of altered sensorium and seizures for 5 days. She was diagnosed
with pulmonary tuberculosis 2 years back and had been treated with WHO-recommended antituberculosis regimen. On examination, she was drowsy and
signs of meningeal irritation were present. The plantar response was bilaterally extensor. Performing investigations, cerebrospinal fluid examination showed a
raised protein, low sugar, and a lymphocytic pleocytosis. The Xpert MTB/RIF detected Mycobacterium tuberculosis with resistance to rifampicin, in
cerebrospinal fluid. The conventional drug susceptibility testing later confirmed resistance to both isoniazid and rifampicin. The chest X-ray revealed haziness
and radio-opacity involving right middle zone, while contrast enhanced MRI of brain revealed meningeal enhancement along with tuberculomas involving left
parietal region (Figure 1a,b). ELISA for HIV was negative. After confirmation of rifampicin resistance, she was started on multidrug-resistant antituberculosis
regimen while awaiting report of conventional drug susceptibility testing. She was given pyrazinamide, levofloxacin, kanamycin, ethionamide, cycloserine, and
ethambutol as per our institutional protocol for multidrug-resistant tuberculosis. She was also given intravenous dexamethasone and antiepileptics. Despite
all our efforts her condition kept on deteriorating; her headache worsened, and she slipped into coma. She died 4 weeks later.

later stages of the disease, the patient is comatose and
demonstrates signs of brainstem dysfunction [50].
Hyponatremia is a common metabolic abnormality. The clin-
ical presentation of drug-resistant tuberculous meningitis
does not substantially differ [41,51,52]. The clinical and neu-
roimaging features of drug-resistant tuberculous meningitis,
as reported in various case reports, are summarized in
Table 3 [53–56] (Box 1 and Figure 1). In pediatric patients,
during early stages, diagnosis of tuberculous meningitis is
often missed. The early clinical manifestations are often non-
specific, like fever, headache, irritability, loss of weight, and
vomiting. In later stages, seizures, raised intracranial pressure,
focal neurological deficits, coma dominate the clinical man-
ifestations [57,58].
According to the British Medical Research Council grading
system, tuberculous meningitis is categorized into three grades.
Grade-I tuberculous meningitis is characterized with a Glasgow
coma scale score of 15 without any focal neurological deficit.
Grade-II is characterized with a Glasgow coma scale score of
11–14 with or without focal neurological deficit. Grade-III tubercu-
lous meningitis is associated with Glasgow coma scale score of 10
or less than 10. This grading system helps in predicting the prog-
nosis [59].
6. Imaging
CT and magnetic resonance imaging, both, are valuable for
the assessment of complications of tuberculous meningitis.
Magnetic resonance imaging, however, is the preferred
method. Neuroimaging characteristics of tuberculous menin-
gitis are basal exudates, hydrocephalus, infarcts, and intracra-
nial tuberculoma [60]. Tuberculomas are quite common and
characterized by homogeneous or ring-enhancing lesions.
They are either solitary, multiple, or miliary, the latter being
common in patients with miliary pulmonary tuberculosis [61].
Similar neuroimaging abnormalities are seen in drug-resistant
tuberculous meningitis as well (Table 3) (Box 1 and Figure 1)
7. Diagnostic dilemmas
A major reason for clinical deterioration in tuberculous menin-
gitis is the paradoxical response to antituberculosis treatment,
which entails worsening of a preexisting tuberculous lesion or
appearance of new symptom/lesions in patients whose condi-
tion initially improved with the treatment. This type of
response occurs in approximately one-third of patients and
generally does not adversely affect the outcome. A wide
variety of paradoxical reactions have been described, includ-
ing expansion of existing cerebral tuberculomas, appearance
of new tuberculomas, hydrocephalus, and optochiasmatic and
spinal arachnoiditis [62].
A clinical deterioration following antiretroviral therapy
(paradoxical worsening) in HIV-infected persons is known as
immune reconstitution inflammatory syndrome. High CSF
neutrophil counts, positive culture of M. tuberculosis and
altered cytokine profile are determinants of tuberculous
meningitis-associated immune reconstitution inflammatory
syndrome in the HIV-infected patients [63]. Concomitant
opportunistic CNS infections like cryptococcal meningitis, cer-
ebral toxoplasmosis, aspergillosis, and neurosyphilis have simi-
lar clinical features and thus pose a diagnostic challenge
[64,65], since multiple microorganisms have been detected in
the brains of about 15% patients [66].
8. Differential diagnosis
Drug-resistant tuberculous meningitis should be suspected if a
patient poorly responds to a primary antituberculosis regimen
or if there is history of close contact with a multidrug-resistant
tuberculosis source case. A history of inadequate and poor
quality antituberculosis treatment, and the presence of disse-
minated tuberculosis, increases the suspicion for drug-resis-
tant tuberculous meningitis.
Drug-resistant tuberculous meningitis needs to be differ-
entiated from other varied causes of acute and subacute
meningitis, like cryptococcal meningitis, viral encephalitis, sar-
coidosis, and carcinomatous and lymphomatous meningitis.
Neoplastic meningitis results from the dissemination of can-
cer cells from solid malignancies, like breast cancer, lung cancer,
and melanoma to leptomeninges. Neurological symptoms seen
in these patients include headache, cranial nerve palsy, lower
extremity weakness, and gait disturbance. Neoplastic meningitis
is diagnosed by demonstrating malignant cells in the CSF [67,68].
Primary diffuse leptomeningeal gliomatosis is an infrequent but
fatal CNS malignancy that presents with a similar clinical picture
to that of tuberculous meningitis, and patients are often treated
erroneously with antituberculosis drugs. Meningeal biopsy is
needed to confirm the diagnosis in these cases [69].
9. Drug susceptibility testing
Rapid microbiological confirmation of tuberculous meningitis
is essential for prompt treatment. Conventionally, smear
microscopy and culture are used for detecting M. tuberculosis
816 R. K. GARG ET AL.

Table 2. Drug resistance profile amongst confirmed cases of tuberculous meningitis across the world along with molecular profile and outcome.
Confirmed Treatment Outcome of
cases with regimen of patients with
Total Method for DST Molecular profile/strain drug resistant drug
Author/year Country subjects confirmation available Resistance pattern identified cases resistance
Gupta et al. 2017 India 478 Culture 287 INH mono- Not mentioned Not 3/24 died
[9] resistance N = 24 mentioned amongst
MDR N = 9 INH
resistant
cases.
6/9 died
amongst
MDR cases
Kaviyil 2017 [5] India 790 Culture on LJ 317 culture INH mono- Not mentioned Not Not
medium. positive resistance N = 15 mentioned mentioned
IS6110 PCR cases SM mono-
LPA. DST resistance N = 10
DST done using carried MDR N = 6
MGIT. out on
191
Vinnard et al. USA 324 Culture. 324 INH mono- Not mentioned Not 18/32 died
2017 [3] DST was done resistance N = 32 mentioned amongst
using BACTEC Rifampicin mono- INH mono
radiometric resistance N = 6 resistance
method. MDR N = 61 cases.
58/61 died
amongst
MDR cases.
Heemskerk et al. Vietnam 817 Culture, 322 INH mono- KatG (70.5%) MDR treated 27/86 died
2017 [123] Xpert MTB/RIF, resistance N = 86 inhA (19.2%) in INH mono- as per DST amongst
DST done using MDR N = 15 resistance INH
MGIT. Rifampicin mono- resistance
resistance N = 1 cases.
11/16 died
in the MDR/
RR group.
Kumar et al. 2016 India 176 Culture on LJ 176 MDR N = 3 Not mentioned Not Not
[51] media; Bactec Mono drug mentioned mentioned
MGIT resistance to any
of the first-line
drugs N = 35
Wang et al. 2016 China 350 Culture 25 MDR N = 3 Beijing strain was common Second-line 2/12 cases
[4] MGIT Mono-resistance drugs with any
N = 12 drug
resistance
died
None of the
MDR cases
died
Kambli et al. 2016 India 205 Culture 63 MDR N = 35 Not mentioned Not Total 17/63
[10] MGIT Rifampicin mono- mentioned deaths, 9 in
resistance N = 6 MDR
INH mono- patients
resistance
N=3
Zhang et al. 2016 China 401 Culture 35 MDR N = 4 mutations at rpoB and katG Modified as 4 drug
[41] MGIT Rifampicin mono- genes per DST resistant
resistance N = 2 patients had
INH mono- poor
resistance outcome
N=6
Senbayrak et al. Europe 142 Culture on LJ 142 INH mono- Not mentioned Not 3/9 died
2015 [11] media. resistance N = 9 mentioned amongst
BACTEC MGIT Ethambutol INH mono
mono-resistance resistance.
N=1 2/5 died
SM Mono- amongst
resistance N = 2 MDR
MDR N = 5 resistance
cases.
Sharma et al. India 110 Culture on LJ 12 Rifampicin rpoB mutation in all 3 cases Not Not
2015 [12] medium. resistance N = 3 with resistance mentioned mentioned
Real time PCR
using IS6110,
MPB64 and
rpoB primers.
(Continued )
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 817

Table 2. (Continued).
Confirmed Treatment Outcome of
cases with regimen of patients with
Total Method for DST Molecular profile/strain drug resistant drug
Author/year Country subjects confirmation available Resistance pattern identified cases resistance
Gupta et al. 2015 India 238 Culture on LJ 89 INH mono- Mutations in rpoB Not Not
[75] medium. resistance N = 7 katG and in inhA genes mentioned mentioned
Geno Type ® MDR N = 4
MTBDR plus Ethambutol
LPA. mono-resistance
BACTEC MGIT N=3
960 SM mono
resistance N = 5
Nhu et al. 2014 Vietnam 379 Xpert MTB/RIF. 151 Rifampicin Not mentioned Not Not
[13] MGIT culture. resistance N = 4 mentioned mentioned
LPA MDR N = 3
Jain et al. 2012 India 370 Culture 51 INH resistance N = 7 Not mentioned Not Not
[14] PCR SM resistance mentioned mentioned
DST by N=5
conventional MDR N = 1
1% proportional
method.
Tho et al. 2012 Vietnam 186 Culture 186 MDR N = 8 15% Indo-Oceanic lineage, Not All the MDR
[120] DST by INH mono- 18% Euro-American mentioned patient
conventional resistance N = 12 lineage, and 67% East died.
1% proportional SM mono Asian/Beijing lineage
method. resistance N = 28
Seddon et al. South 123 Culture and 123 INH mono- 37 Beijing strains. Second-line0/10 deaths in
2012 [15] Africa conventional resistance N = 10 drugs INH
DST. Rifampicin Mono- resistant
GenoType resistance N = 1 cases.
MTBDRplus MDR N = 5 1/1 deaths
line probe in R
assay, resistant
cases.
4/5 deaths
in MDR
cases.
Duo et al. 2011 China 123 Culture 28 INH mono- rpoB mutations in 90.91% for Not Not
[16] BACTEC MGIT. resistance N = 9 rifampicin katG315 for mentioned mentioned
PCR and Rifampicin Mono- 77.78%
MTBDRplus resistance N = 2 INH resistance
assay MDR N = 9
Vinnard et al. USA 3114 Culture and DST 1683 MDR N = 26 Not mentioned Second-line 19/26 deaths
2011 [17] drugs in MDR
patients
Vinnard et al. USA 1649 Culture and DST 1649 Resistance to at Not mentioned Not Not
2011 [7] least one first- mentioned mentioned
line drug N = 234
INH resistance
N = 133
Vinnard et al. USA 1896 Culture and DST 1614 INH resistance Not mentioned Not 43/123 with
2010 [111] N = 123 mentioned initial H
resistance
died;
29 subjects
with MDR
were
excluded
Yorsangsukkamol Thailand 158 Culture and DST 158 INH mono- Beijing strain N = 88 Not Not
et al. 2009 [18] by proportional resistance N = 7 mentioned mentioned
method SM mono-
resistance N = 8
MDR N = 8
Nagarathna et al. India 366 BACTEC 460TB 366 INH resistance Not mentioned Not Not
2008 [19] culture N = 46 mentioned mentioned
MDR N = 9
Torok et al. 2008 Vietnam 58 Culture and DST 46 Resistance to one or Not mentioned Not Not
[118] HIV by MGIT more first-line mentioned mentioned
drugs N = 25
Mono-resistance
to one first-line
drug N = 6
MDR N = 4
(Continued )
818 R. K. GARG ET AL.

Table 2. (Continued).
Confirmed Treatment Outcome of
cases with regimen of patients with
Total Method for DST Molecular profile/strain drug resistant drug
Author/year Country subjects confirmation available Resistance pattern identified cases resistance
Caws et al. 2007 Vietnam 198 Proportion 198 MDR N = 6 Mutations Not Not
[6] method Mono-resistance in katG:26; mentioned mentioned
N = 36 inhA: 11;
rpoB: 6
Cecchini et al. Argentina 101 Löwenstein– 101 MDR N = 42 Not mentioned Not 64/101 died
2007 [20] Jensen Mono-resistance mentioned
medium or N=7
BACTEC;
proportion
method;
BACTEC
radiometric
method
Padayatchi et al. South 8 Not stated 8 Mono-resistance N Not mentioned Second-line 7/8 died
2006 [53] Africa =1 drugs
MDR N = 7
Thwaites et al. Vietnam 180 Proportion 180 MDR N = 10 Not mentioned No second- 10/10 MDR
2005 [52] method INH mono- line drug patient
resistance N = 9 given. died.
SM mono- 2/9 INH
resistance N = 24 mono-
Resistant to INH resistant
and SM only patient
N = 28 died.
4/24 SM
mono-
resistance
patients
died
Patel et al. 2004 South 30 Not mentioned 30 MDR N = 30 Not mentioned Second-line 17/30 died
[54] Africa drugs
Thwaites et al. Vietnam 56 Culture 56 INH mono- Beijing N = 16 No second No effect on
2002 [8] MGIT resistance N = 9 Vietnam N = 6 line used outcome
SM mono-
resistance N = 10
DR: drug resistance; DST: drug susceptibility testing; INH: isoniazid; LMGIT: mycobacterial growth indicator tube; J: Löwenstein Jensen; MDR: multidrug resistant;
N: number; PCR: polymerase chain reaction; R: rifampicin; SM: streptomycin.

Figure 1. Chest X-ray posterior-anterior view showing haziness in right middle zone. (a) Post-contrast T1 image showing ring-enhancing lesions suggestive of
tuberculoma in left parietal region.

in the CSF. Drug susceptibility testing is crucial in guiding the
physician to choose the best antituberculosis drug regimen. It
is performed either by molecular genotypic techniques or
phenotypic testing on M. tuberculosis isolates. Genotypic test-
ing yields quick results, which expedite the clinician’s decision.
A large CSF volume (more than 6 ml) gives better results. [70]
Reliable tuberculosis drug susceptibility tests for isoniazid,
rifampicin, fluoroquinolones, and second-line injectable
agents are widely available. Conventional drug susceptibility
testing for ethambutol is often unreliable, and molecular
screening for mutations in the embB gene is preferred [71].
Drug susceptibility testing for pyrazinamide is largely not
available in resource-constrained countries. In many countries,
rifampicin-resistant strains frequently have additional resis-
tance to pyrazinamide. Mutations in inhA promoter genes
confer resistance to isoniazid and ethionamide/prothiona-
mide. Drug susceptibility testing for many uncommonly used
drugs, like clofazimine, amoxicillin/clavulanate, clarithromycin,
azithromycin, linezolid, and thioacetazone, is not routinely
performed. A very limited number of countries have the facil-
ity for drug susceptibility tests for many drugs, with limited
data about their safety and efficacy, like clofazimine, ethiona-
mide/prothionamide, and carbapenems [72].
9.1. Methods available for drug susceptibility testing
9.1.1. Conventional methods
Löwenstein–Jensen solid medium and fully automated liquid
culture system are conventionally used for microbiological
confirmation and drug-susceptibility testing. The BACTEC
MGIT 960 liquid culture system is fully automated and uses
the fluorescence of an oxygen sensor to detect mycobacterial
growth in culture media. Culture-based methods, however,
take 2–6 weeks to yield results.
9.1.2. Nucleic acid amplification tests
Nucleic acid amplification tests that detect mutations confer-
ring resistance to antituberculosis drugs have significantly
advanced and expedited tuberculosis diagnosis [73]. These
genotypic tests can be used to determine drug susceptibility.
9.1.3. Line probe assays
Line probe assays are designed to simultaneously identify M.
tuberculosis complex and detect resistance-conferring muta-
tions. M. tuberculosis complex defines a group of mycobacteria
that are 99.9% similar at the nucleotide level and have iden-
tical 16S rRNA sequences but differ in host tropism and patho-
genicity [74]. The line probe is a highly sensitive and specific
assay for identifying drug resistance to isoniazid and rifampi-
cin in M. tuberculosis culture isolates [75]. They are based on
multiplex polymerase chain reaction (PCR) and reverse hybri-
dization techniques for the rapid detection of mutations in
antibiotic resistance genes, like rpoB, katG, and inhA, or any
deletion in wild-type gene loci. The approximate turnaround
time for line probe assay results is 2–3 days. There are, how-
ever, certain drawbacks of these tests. First, the open-tube
format of these tests enhances the risk of cross-contamination
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 819
and false positive results. Secondly, they are not useful for
detecting M. tuberculosis and resistance patterns if performed
directly on CSF specimens from confirmed tuberculous menin-
gitis cases [75]. Commercially available DNA line probe assays
include GenoType MTBDRplus and MTBDRsl assays (Hain
Lifescience GmbH, Germany), and INNO-LiPA Rif.TB line
probe assay (Innogenetics Inc., Belgium).
9.1.4. Xpert MTB/RIF
Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is a WHO-
approved automated PCR-based technique that utilizes the
GeneXpert platform. It can detect both M. tuberculosis
complex and rifampicin resistance. The approximate turn-
around time for results is 2–3 hours. It is a cartridge-based
NAAT (CBNAAT) technology that uses a separate cartridge
for each test, thus minimizing the risk of cross-contamina-
tion. Xpert MTB/RIF identifies rifampicin-resistant muta-
tions in the rpo-β gene but does not identify isoniazid
resistance. However, a positive test for rifampicin resis-
tance can be a surrogate marker for isoniazid resistance,
since more than 90% of rifampicin-resistant strains are
resistant to isoniazid as well [73]. WHO recommends
Xpert MTB/RIF as the initial diagnostic test for CSF over
conventional tests, along with CSF centrifugation [76]. If
Xpert MTB/RIF testing turns out negative, conventional
testing should be performed [77].
9.1.5. Xpert MTB/RIF ultra
The WHO recently recommended Xpert MTB/RIF Ultra
(Cepheid, Sunnyvale, CA, USA), a next-generation Xpert®
MTB/RIF assay. The Ultra cartridge has demonstrated distinctly
better performance and is able to detect even low numbers of
M. tuberculosis. In addition, Ultra cartridge has a larger cham-
ber for DNA amplification, which can accommodate larger
specimen volumes and has two additional molecular targets
to detect tuberculosis [78]. Xpert Ultra has proven to be more
sensitive in detecting tuberculous meningitis compared to the
earlier version of Xpert MTB/RIF or conventional culture. In a
prospective study, among 129 HIV-infected adults with tuber-
culous meningitis (23 probable or definite cases), Xpert Ultra
sensitivity was 70% (16 of 23 cases) for probable or definite
tuberculous meningitis compared with 43% (10/23) with Xpert
and 43% (10/23) with culture [79]. Xpert MTB/RIF Ultra is being
considered a ground-breaking development in tuberculosis
diagnosis, but more data is needed before widely recom-
mending this test [80].
9.1.6. GenoType MTBDRsl assay
Second-line line probe assays can be used to detect additional
resistance to second-line drugs after rifampicin-resistance or
multidrug-resistance has been established. MTBDRsl sensitivity
and specificity were 97% and 98% for smear-positive, and 80%
and 100% for the smear-negative specimens [81]. GenoType
MTBDRsl assay has not been evaluated in CSF specimens so
far. A new investigational assay cartridge, designed for phe-
notypic drug-susceptibility testing and sequencing of katG,
gyrA, gyrB, and rrs genes, and of the eis and inhA promoter
 820

Table 3. Summaries of various case reports and case series describing clinical and neuroimaging features of drug-resistant tuberculous meningitis, along with treatment regimen and outcome.
Extra CNS
Reference Country Age/sex HIV Status Site/mode of resistance Clinical features involvement Imaging features Treatment outcome
Kaplan et al. United 28 M Indian* Negative XDR-TB Disseminated tuberculosis Pulmonary Two tuberculomas Second-line drugs for 24 months improved
2018 [55] States Lymph node in frontal lobe
Spine and medulla
Akkerman et al. United 30 M Negative MDR Tuberculous meningitis None NA Second-line drugs and bedaquiline NA
2016 [84] States Somalia*
R. K. GARG ET AL.

Sharma et al. India 7F Negative XDR-TB in CSF Tuberculous meningitis None Obstructive Clarithromycin, second-line drugs improved
2016 [21] hydrocephalus
2F Negative XDR-TB in CSF Tuberculous meningitis Pulmonary Multiple infarcts Second-line drugs improved
and obstructive
hydrocephalus
3F Negative XDR-TB in gastric Tuberculous meningitis Pulmonary Obstructive Second-line drugs improved
lavage hydrocephalus
with infarct
Alsleben et al. South 4F Negative XDR-TB in Tuberculous meningitis Abdominal Meningeal Isoniazid, rifampin, pyrazinamide, improved
2015 [100] Africa Ascitic fluid tuberculosis enhancement, ethionamide failed and had
(Tuberculous ring-enhancing hepatotoxicity
peritonitis) lesions, Second-line drugs given
multiple
infarcts, and
hydrocephalus
with
progressive
worsening
Yoo et al. 2014 South 27 M Positive MDR-TB in sputum and Disseminated military tuberculosis Pulmonary and Not done Levofloxacin and amikacin with first line improved
[22] Korea CSF skin drugs
tuberculosis
Sharma et al. India 20F Negative Provisional Tuberculous meningitis None Normal Cycloserine and levofloxacin was added Cycloserine-
2014 [23] diagnosis to first line drugs induced
psychosis
Improved
Bernard et al. France 34 M Negative MDR in sputum and Disseminated tuberculosis (brain, Pulmonary and Not done Second-line treatment improved
2014 [24] drug-sensitive lungs and lymph nodes) lymph node
phenotype in CSF
Mauro et al. Italy 3M Negative MDR in CSF Tuberculous meningitis None Basal First-line drugs later changed to second NA
2012 [25] meningeal line drugs
enhancement
and
hydrocephalus
Ikegame et al. Japan 63 M with Not done Isoniazid resistance in Miliary tuberculosis with Miliary pulmonary Normal First-line drugs later levofloxacin added improved
2011 [26] leukemia sputum tuberculous meningitis tuberculosis in place of Isoniazid
Marschall et al. Switzerland 48 M Positive MDR in CSF Disseminated Pulmonary Multiple infarcts Isoniazid,
2008 [27] Tuberculosis Bone and joint ethambutol,
with
tuberculous
meningitis and
femoral
osteomyelitis
pyrazinamide, Died
and
moxifloxacin.
(Continued )
Table 3. (Continued).
Extra CNS
Reference Country Age/sex HIV Status Site/mode of resistance Clinical features involvement Imaging features Treatment outcome
Kohli and Kapoor India 46 M Not done MDR in CSF Tuberculous meningitis with None Multiple Cycloserine, ethionamide, Not mentioned
2008 [28] progressive headache tuberculomas pyrazinamide, kanamycin
in the MCA
territory
Meybeck et al. France 30F Positive MDR in sputum Disseminated Pulmonary Cerebral infarcts First-line drugs later amikacin, Died
2007 [29] tuberculosis with meningitis and P-aminosalycylic acid and
lymphadenopathy moxifloxacin, ethionamide added
30F Positive Resistance Disseminated Chest Meningeal Isoniazid dose Improved after
to streptomycin, and tuberculosis with meningitis and Abdomen enhancement was increased and moxifloxacin was 6 months
isoniazid in sputum lymphadenopathy Lymph nodes added
later
Second-line drugs
Ersoy et al. 2007 Turkey 19 M Negative Abscess material INH- Tuberculous meningitis Spinal cord Left cerebellar First-line drugs later second-line drugs improved
[30] resistant hemisphere added
tuberculoma
extending to
the spinal cord
and
syringomyelia
Padayatchi et al. South 8 children 6 positives MDR either in sputum, Pulmonary Pulmonary Meningeal First-line drugs, in some cases Seven children
2006 [53] Africa (2–11; 5M CSF or stool tuberculosis with tuberculous enhancement, fluoroquinolones died
and 3F) (3 in CSF) meningitis and tuberculoma,
lymphadenopathy hydrocephalus
and infarcts
Ripamonti et al. Africa 27 F with negative Culture of biopsied Pulmonary tuberculosis in past Pulmonary Large intracranial Isoniazid, morfazinamide, rifampin, and improved
2004 [31] pregnancy brain tuberculous meningitis tuberculoma ethambutol
tissue resistant to
isoniazid
37 M negative Sputum to isoniazid Pulmonary tuberculosis with Pulmonary Multiple occipitotemporal Isoniazid,
and streptomycin tuberculous meningitis tuberculomas region rifampin,
in ethambutol,
and
pyrazinamide
improved
Patel et al. 2004 South 30 patients 28 positives MDR in CSF (29) sphenoidal biopsy Pulmonary Pulmonary Not much details First-line drugs
[54] Africa (0.4– specimen (1) tuberculosis tuberculosis in later
45 years; (14) 14 cases second-line
21F) tuberculous drugs
meningitis was added
Either died or
had major
disabilities
Daikos et al. Greece 8 cases (28– Positive MDR-TB in sputum Miliary or pulmonary TB preceded Miliary pulmonary Imaging Details are not provided Seven patients
2003 [32] 45; 5M the in all patients abnormality in died
and 3F) 7 – meningeal
enhancement,
tuberculoma,
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY

hydrocephalus
and infarcts
(Continued )
821
 822
R. K. GARG ET AL.

Table 3. (Continued).
Extra CNS
Reference Country Age/sex HIV Status Site/mode of resistance Clinical features involvement Imaging features Treatment outcome
Sofia et al. 2001 South 22M Negative MDR Pericardial fluid Pericardial and plural effusion and Pleural and tuberculoma brain Second-line drugs improved
[33] Africa and CSF tuberculous meningitis pericardial
16 M Negative MDR-TB in sputum Lymphadenopathy, pulmonary Pulmonary and Not done Second-line drugs Died
tuberculosis and tuberculous lymph node
meningitis
21 F Negative MDR in CSF Lymphadenopathy, pulmonary Lymph node Normal Second-line drugs Died
tuberculosis and tuberculous And pulmonary
meningitis
Silber et al. 1998 South 32 M Positive MDR in CSF Tuberculous meningitis None Not done First-line drugs later second-line drugs Died
[34] Africa
Horn et al. 1993 USA 34 M Positive MDR in CSF Tuberculous meningitis None Hypodensity with Patient died before confirmation Died
[35] mass effect
Watt et al. 1989 Philippines 44 M Not mentioned Resistant to isoniazid and Tuberculous Pulmonary Not mentioned Patient died
[56] streptomycin in CSF meningitis and tuberculosis before
past pulmonary confirmation
TB
Died
*CSF: cerebrospinal fluid; F: female; M: male; MCA: middle cerebral artery; MDR: multidrug-resistant; NA: not available; TB: tuberculosis; XDR-TB: extensively drug-resistant tuberculosis

regions, is currently under evaluation. Preliminary results sug-
gest that this assay can accurately identify M. tuberculosis
mutations associated with resistance to isoniazid, fluoroquino-
lones, and aminoglycosides [82].
10. Treatment
Current WHO-recommended treatment for tuberculous meningi-
tis caused by drug-susceptible mycobacteria consists of an initial 2-
month intensive regimen of isoniazid, rifampicin, pyrazinamide,
and ethambutol, followed by a 10-month continuation phase of
standard isoniazid and rifampicin regimen [83]. Isoniazid is the
mainstay of this treatment due to its excellent bactericidal activity
and CSF penetration. Pyrazinamide also has excellent CSF penetra-
tion and is used as a sterilizing drug in the initial 2 months.
Ethambutol and streptomycin have no CSF penetration and play
only supporting roles.
Drug-resistant tuberculous meningitis has an enhanced risk
of treatment failure and death in patients who receive first-line
regimens. Isoniazid resistance deprives patients of the benefit
of the most effective antituberculosis drug [3]. The optimum
antituberculosis drug regimen for multidrug-resistant tubercu-
lous meningitis is largely unknown, and only isolated case
reports are available regarding second-line antituberculosis
drug resistance. For multidrug-resistant tuberculous meningi-
tis, alternative drugs with adequate CSF penetration are
required. Therefore, drug susceptibility results are in valuable
in formulating an adequate antituberculosis drug regimen [1].
Nevertheless, WHO-recommended regimens against multi-
drug-resistant pulmonary tuberculosis can very well be extra-
polated for resistant tuberculous meningitis.
The WHO recently identified antituberculosis drugs that
have a definite role in the treatment of multidrug-resistant
tuberculosis under controlled conditions [1]. The latest classi-
fication of these drugs, their CSF penetration, and their role in
tuberculous meningitis have been summarized in Table 4 [84].
Fluoroquinolones (levofloxacin, moxifloxacin, and gatifloxacin)
are the most favored drugs due to their excellent CSF pene-
tration [85].
An antituberculosis drug regimen containing a later-gen-
eration fluoroquinolone (levofloxacin, moxifloxacin, or gati-
floxacin) may halve the risk of mortality in drug-resistant
tuberculosis. [94] Unfortunately, the inclusion of levofloxacin
in antituberculosis regimen may not translate to a better out-
come, and moxifloxacin has not shown a clear relationship
with survival [86,95,96]. Fluoroquinolones are associated with
a risk of QT -interval prolongation, and a large proportion of
multidrug-resistant M. tuberculosis strains have simultaneous
fluoroquinolone resistance [97]. Given the pros and cons,
fluoroquinolones, because of their good CSF penetration pro-
file, should always be a part of multidrug-resistant tuberculous
meningitis treatment regimen. [85,94]
Second-line injectable drugs (amikacin, capreomycin, or
kanamycin) are integral components of multidrug-resistant
tuberculosis treatment regimen, despite their limited CSF
penetration. The second-line injectable agents penetrate the
CSF only in the acute inflammatory phase. Kanamycin is the
initial injectable drug of choice since CSF penetration of
capreomycin is largely unknown [98] and ototoxicity is a
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 823
major concern with aminoglycosides usage. The group desig-
nated as ‘other core second-line agents’ includes some anti-
tuberculosis drugs with excellent CSF penetration.
Ethionamide/prothionamide, cycloserine/terizidone, and line-
zolid have all been used in multidrug-resistant tuberculous
meningitis. The safety profile of these drugs is a critical factor,
and side effects need to be monitored. While cycloserine is
frequently associated with psychosis and seizures [99], little is
known about terizidone efficacy in tuberculous meningitis
[100]. In South Africa, ethionamide-containing regimen was
associated with excellent results in children with drug-suscep-
tible tuberculous meningitis [101]. Ethionamide can be used
interchangeably with prothionamide, and terizidone can be
used in place of cycloserine. Linezolid improved the early
outcome of childhood tuberculous meningitis [102], and its
strong bactericidal activity and adequate CSF penetration
make it a promising option for multidrug-resistant tuberculous
meningitis [103]. However, it is sometimes associated with
optic atrophy and retinitis, leading to vision loss [104,105].
The role of clofazimine in the management of tuberculous
meningitis is unexplored so far, and no data is available
regarding its CNS penetration.
Para-aminosalicylic acid and ethambutol are not effective
drugs to treat multidrug-resistant tuberculous meningitis as
they have no or low penetration in the CNS. Para-aminosa-
licylic acid penetration may be increased in CSF if it is given in
entirety as a single daily dose. Imipenem–cilastatin, merope-
nem, and amoxicillin-clavulanate have never been tested in
tuberculous meningitis and, therefore, cannot be considered
as a viable treatment option. Bedaquiline and delamanid are
two novel drugs that are being tested. A study in rats showed
penetration of delamanid in CSF. Human data about its CSF
penetration is needed before delamanid is tried for drug-
resistant tuberculous meningitis. [106] Imipenem has good
CSF penetration, but its role in tuberculous meningitis is
unexplored. Children with bacterial meningitis treated with
Imipenem had a risk of recurrent seizures [107].
Pyrazinamide reduces the relapse rates of isoniazid-resistant
pulmonary tuberculosis to 1% if administered continuously
throughout 6 months, as opposed to 7% when given only
for 2 months [108]. It is an important drug in tuberculous
meningitis due to its excellent CSF penetration profile, but
multidrug-resistant M. tuberculosis isolates may also be resis-
tant for pyrazinamide. Mutations in the pncA gene, that con-
fers pyrazinamide resistance, were demonstrated in 70% of
multidrug-resistant and 96% of extensively drug-resistant M.
tuberculosis isolates [109].
Updated guidelines of WHO recommend at least five effec-
tive antituberculosis drugs for multidrug-resistant tuberculosis
regimen during the intensive phase. They include pyrazina-
mide and four core second-line drugs (one from Group A, one
from Group B, and at least two from Group C). Intensive phase
lasts for 8 months, while the continuation phase lasts for a
minimum of 12 months for the oral agents, making the total
duration of treatment 20 months. An ideal multidrug-resistant
tuberculosis regimen, therefore, consists of pyrazinamide, a
fluoroquinolone, an injectable antituberculosis drug, ethiona-
mide (or prothionamide), and cycloserine, or para-aminosa-
licylic acid if cycloserine cannot be used. A shorter regimen
824 R. K. GARG ET AL.
with seven drugs and a treatment duration of 9–12 months
has recently been recommended by WHO but is not recom-
mended for extra-pulmonary disease [1]. Current WHO recom-
mendations mandate that an appropriate regimen for
multidrug-resistant meningitis should consist of a fluoroqui-
nolone (levofloxacin or moxifloxacin), ethionamide and/or
cycloserine, pyrazinamide, an injectable drug (kanamycin or
amikacin) as a supportive drug, and linezolid, despite the
limited evidence for the latter drug. Most of these drugs
have an excellent CSF penetration profile. (Table 4) An algo-
rithm for the diagnosis and management of drug-resistant
tuberculous meningitis are shown in Figure 2.
10.1. Isoniazid mono-resistance
Isoniazid resistance is a major concern since it is the most
effective drug against tuberculous meningitis. In isoniazid-
resistant tuberculosis, treatment with first-line drugs usually
results in suboptimal outcomes [110] and is associated with a
high mortality [111]. Isoniazid resistance is caused by muta-
tions in either katG genes, which confer a high-level resis-
tance, or the inhA promoter genes, which leads to a low-
level resistance with simultaneous cross-resistance to ethiona-
mide. Current guidelines recommend that in case of isoniazid-
resistant pulmonary tuberculosis, isoniazid should be replaced
with a fluoroquinolone and the regimen be continued for 6–
12 months. High-dose isoniazid is of value in patients with
low-level isoniazid resistance. Fluoroquinolone is a good repla-
cement option in isoniazid mono-resistant tuberculous menin-
gitis as well [1].
A recently of published data evaluated the influence of M.
tuberculosis drug resistance on the outcome of tuberculous
meningitis [123]. In the original study, patients were rando-
mized to receive either a standard antituberculosis regimen
with an intensified regimen (higher-dose rifampicin 15 mg/kg/
day and levofloxacin 20 mg/kg/day) for the first 8 weeks or a
standard antituberculosis regimen. The 9-month survival rate
Figure 2. An algorithm suggesting management of drug-resistant tuberculous meningitis. H: Isoniazid; R: Rifampicin; E: Ethambutol; Z: Pyrazinamide;
S: Streptomycin; FQs: Fluoroquinolones; SL: second line, MDR: multidrug resistance; TBM: tuberculous meningitis; CT: computed tomography.
was the endpoint. In this study, 817 patients (322 with a
known drug resistance profile) were randomized. One-hun-
dred and two patients (isoniazid resistance 86, multidrug
resistance 15, and rifampicin monoresistance 1) had some
form of drug resistance. Approximately, 31.4% (27 of 86) of
patients in the isoniazid resistance category and 68.8% (11 of
16) in the multidrug-resistant category died. Therefore, the
intensified regimen improved survival in isoniazid-resistant
tuberculous meningitis only [123]. Recent trials are currently
contemplating the use of a higher rifampicin dosing of
>30 mg/kg in adults. A high dose of rifampicin would poten-
tially increase CSF penetration of rifampicin, and this can
potentially overcome the concern of isoniazid mono-resis-
tance as well. [112]
10.2. Children
Drug-resistant tuberculosis in children is caused by transmis-
sion of a resistant strain from an adult. It is essential to search
for a history of contact with adults in case of drug-resistant
tuberculosis. The treatment of drug-resistant tuberculous
meningitis in children is guided by the same principles as for
adults. The pediatric regimen should also include at least five
effective antituberculosis drugs (pyrazinamide and four core
second-line drugs) during the intensive phase [1].
10.3. Pregnant women
There is some concern over the teratogenic potential of the
second-line antituberculosis drugs. Aminoglycosides are toxic
to the fetal ear, and ethionamide is associated with fetal
growth retardation, and CNS and skeletal abnormalities in
animals. The risk of birth defects is highest in the first trimester
of pregnancy. Continued fetal monitoring is mandatory, and
longer antituberculosis regimen in pregnant women should
consist of four or more effective second-line drugs without
any teratogenic effect [1]. Women of childbearing age should
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 825

Table 4. Dosage, route of administration, cerebrospinal fluid penetration, and adverse effects of multidrug-resistant tuberculosis drugs, as per World Health
Organization [1].
Bacteriostatic/ Route of Common/severe Role in DR-
Drug bactericidal Dose administration CSF penetration adverse events TBM Reference
Group A: Fluoroquinolones
Levofloxacin Bactericidal Adults: 10-15 mg/kg OD Oral or IV Good Nausea Most Van Toi et al.
Children 0–5 years: 16–20% Headache important 2017 [85]
15-20 mg/Kg in 2 divided (93–99% in Dizziness drugs in
doses inflamed Prolonged QTc MDR
Children 5–15 years: 15mg/ meninges) Hypoglycaemia tuberculous
kg OD Rarely tendon meningitis
rupture
Pregnancy is a
relative
contraindication
because of
teratogenic
potential
Moxifloxacin Bactericidal 400 mg OD Oral or IV Nausea Most Alffenaar
Renal failure: No dose Diarrhoea important et al. 2009
adjustment needed Rarely tendon drugs in [87]
rupture MDR
Dysglycaemia tuberculous
QTc prolongation meningitis
Gatifloxacin Bactericidal 400 mg OD Oral Headache No role in TBM
Renal failure: if Crcl < 30 ml/ Malaise
min, 400 mg 3 times a week Insomnia
Diarrhoea
Rare tendon
rupture
Dysglycaemia
Group B: Second-line injectable agents
Amikacin Bactericidal 15 mg/kg/day IV or IM Penetration is good Nephrotoxicity Used in the Donald 2010
Children 15–22.5 mg/kg/ in presence of Ototoxicity intensive [88]
day meningeal Vestibular toxicity phase
inflammation Electrolyte
imbalance
Capreomycin Bactericidal 15 mg/kg/day IV or IM Data not available Nephrotoxicity Used in the Donald 2010
Children 15–30 mg/kg/day Ototoxicity intensive [88]
Vestibular toxicity phase
Electrolyte
imbalance
Kanamycin Bactericidal 15 mg/kg/day OD IV or IM Variable; better Nephrotoxicity Used in the Donald 2010
Children 15–30 mg/kg/day penetration in Ototoxicity intensive [88]
the presence of Vestibular toxicity phase
meningeal
inflammation
Streptomycin Bactericidal 15 mg/kg/day IV or IM Variable; better Nephrotoxicity Used in the Donald 2010
penetration in Ototoxicity intensive [88]
the presence of Vestibular toxicity phase
meningeal Electrolyte
inflammation imbalance
Group C: Other core second-line agents
Ethionamide/ Weakly 15-20 mg/kg/day in divided Oral Good G.I upset Important Donald 2010
Protionamide bactericidal doses (100%) Anorexia drugs in [88]
Usually 500–750/day in 2 Hepatotoxicity MDR TB
divided doses Neurotoxicity meningitis
Gynaecomastia
Impotence
Hair loss
Cycloserine/ Bacteriostatic 10-15 mg/day in 2 divided Oral Good Lethargy Important Donald 2010
terizidone doses (maximum 1000mg) (79%) Depression drugs in [88] and
Seizures MDR TB Goff et al.
Psychosis meningitis 1999 [89]
Neuropathy
Linezolid Bactericidal 600 mg once a day Oral or IV Fair Bone marrow An important Tsona et al.
Children 10 mg/kg/day OD (70%) suppression option for 2010 [90]
(limited use) Diarrhoea MDR-TB
Optic neuropathy meningitis
Peripheral
neuropathy
(Continued )
826 R. K. GARG ET AL.
be strongly advised to use contraception during the treatment
regimen.
10.4. Corticosteroids therapy
Corticosteroids are now part of the standard care of tubercu-
lous meningitis. They significantly improve survival and dis-
abilities amongst survivors [113]. However, the role of
corticosteroids has not been separately evaluated in drug-
resistant tuberculous meningitis. The largest study that
included 545 patients, a major contributor to Cochrane recom-
mendations, had in fact included a sizable number of drug-
resistant tuberculous meningitis patients. Among 170 isolates,
60 isolates were resistant to streptomycin, isoniazid or both,
and 11 isolates had multidrug resistance [114].
11. HIV and drug-resistant tuberculous meningitis
An increased frequency of drug-resistance has also been
noted in HIV-infected patients with tuberculous meningitis
[3]. HIV-positive patients are at an increased risk of drug-
resistant tuberculosis. Multidrug-resistant tuberculosis in
this population is associated with wide dissemination,
poor outcome, and higher mortality [115,116]. A
Vietnamese study, via drug-susceptibility testing of CSF
isolates, demonstrated that 47.5% (19/40) of HIV-infected
patients were resistant to one or more first-line antituber-
culosis drugs, compared to 39.1% (50/128) of non-HIV
patients [117]. Another Vietnamese study on HIV-asso-
ciated tuberculous meningitis demonstrated that 54%
(25/46) of CSF isolates were resistant to one or more
first-line drugs, and 9% had multidrug resistance. The mor-
tality rate in patients with multidrug-resistant tuberculous
meningitis is 100%[118]. Many resistant HIV-associated
tuberculous meningitis cases have concomitant pulmonary
miliary tuberculosis [119]. There are at present divergent
views on tuberculosis mono-resistance in HIV patients.
Torok et al. did not observe the adverse impact of strep-
tomycin and/or isoniazid mono-resistance among HIV
infected patients [118]. In contrast, Tho et al. noted that
isoniazid mono-resistance had an adverse impact in HIV-
associated tuberculous meningitis patients [120].
HIV-infected drug-resistant tuberculous meningitis
patients should be given similar antituberculosis regimen
as for non-HIV cases. WHO mandates that in HIV patients
with pulmonary tuberculosis, antiretroviral therapy should
be started promptly regardless of the CD4 cell count.
Second-line antituberculosis drugs should be given first,
and antiretroviral therapy should be administered as soon
as the former is tolerated. Generally, this is done within the
first 2 weeks [1]. However, antiretroviral therapy is deferred
for approximately 6–8 weeks in tuberculous meningitis
patients, as early initiation of antiretroviral therapy does
not improve outcome. It may, instead, lead to a serious
CNS immune reconstitution inflammatory syndrome (like
fatal opportunistic infection or neurological deterioration
or death) simulating failure of second-line antituberculosis
drugs [121,122]. In patients with HIV infection and drug-
resistant tuberculosis, treatment with antiretroviral therapy
is likely to have an overlapping and potentially additive
adverse effect profile with the antituberculosis drugs.
12. Prognosis
Drug-resistant tuberculous meningitis is associated with a
poor prognosis [7,120] and a high mortality rate. Vinnard
et al. assessed the long-term survival and noted that out of
225 drug-susceptible tuberculous meningitis patients, 102
(45%) died, while 58 (95%) died among the 61 patients
with multidrug-resistant tuberculous meningitis [3]. Early
intensified antituberculosis treatment improved survival in
patients with isoniazid-resistant tuberculous meningi-
tis [123].
13. Conclusion
With the widespread availability of newer Xpert® MTB/RIF
assay technology, an increasing number of patients with
drug-resistant tuberculous meningitis are being diagnosed.
Xpert MTB/RIF Ultra is considered by many experts to be a
breakthrough in tuberculosis diagnostics. Although inten-
sified antituberculosis treatment regimen has provided
hope for isoniazid mono-resistant tuberculous meningitis,
the fate of multidrug-resistant tuberculous meningitis
remains bleak. The role of second-line antituberculosis
drugs with adequate CSF penetration need to be explored
in randomized controlled studies. An effective tuberculosis
control and prevention program is necessary to curb the
increasing challenge of drug-resistance in tuberculous
meningitis cases. Rapid identification and prompt initiation
of effective antituberculosis treatment is crucial in render-
ing drug-resistant tuberculosis cases noninfectious.
14. Expert commentary
Drug-resistant tuberculous meningitis is a life-threatening
condition and requires a rapid and reliable diagnosis for
prompt treatment. Xpert MTB/RIF Ultra technology is now
available that can detect tuberculous meningitis and rifam-
picin resistance even when the CSF contains low numbers
of the bacilli. Wider availability of Xpert MTB/RIF Ultra is
needed in the next five years, particularly in the high
tuberculosis zones. This will help in identifying multidrug-
resistant tuberculous meningitis and enable physicians to
start an appropriate treatment with second-line drugs.
The second issue is that currently available antitubercu-
losis drug regimens meant for multidrug-resistant tubercu-
losis are far from satisfactory for the treatment of multidrug-
resistant tuberculous meningitis. Currently, the latter
requires prolonged and expensive treatment. Many second-
line drugs also have unacceptable side effects. Three
recently licensed drugs – bedaquiline, delamanid, and pre-
tomanid – do not penetrate the CNS, but it is premature to
dismiss them based solely on their unfavorable CSF penetra-
tion profile. More robust pharmacokinetic studies are
required to clarify this aspect. There is an urgent need for
newer antituberculosis drugs with an adequate CSF
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 827

Table 4. (Continued).
Bacteriostatic/ Route of Common/severe Role in DR-
Drug bactericidal Dose administration CSF penetration adverse events TBM Reference
Clofazimine In vitro activity mycobacterium 100-200 mg/ Oral Data not available Discolouration
against day of skin and
Children urine
1mg/kg/ GI
day OD intolerance
(limited
use)
Photosensitivity Limited role in Holdiness et al. 1989 [91]
QTc MDR-TB
prolongation meningitis
Retinopathy
Group D: Add on agents
D1 Pyrazinamide Bactericidal 25 mg/kg/day maximum Oral Good Hyperurecemia and First-line drug Donald 2010
2000 mg (100%) gout for [88],
Children 30-40 mg/kg/day Hepatotoxicity tuberculous Phuapradit
Rash meningitis et al. 1990
GI upset [92], Ellard
et al. 1987
[93]
D1 Ethambutol Bacteriostatic 15 mg/kg/day Oral Poor Optic neuritis First-line drug Donald 2010
for [88],
tuberculous Phuapradit
meningitis et al. 1990
[92], Ellard
et al. 1987
[93]
D1 High Dose Bactericidal 4-6 mg/Kg/day Oral Good Hepatotoxicity First-line drug Donald 2010
Isoniazid High dose isoniazid (600mg) Neuropathy for [88],
can be used for low-level tuberculous Phuapradit
isoniazid resistance other meningitis et al 1990
than due to katG mutation. [92], Ellard
et al. 1987
[93]
D2 Bedaquiline Bactericidal 400 mg OD initially, then Oral No data available GI distress Part of short Akkerman
200 mg 3 times per week QTc prolongation intensified et al. 2016
(limited use in children) Increased risk of treatment [84]
pancreatitis in children
Joint pain
D2 Delamanid Inhibits 100 mg BD Oral No data available Nausea No definite
synthesis of (limited use in children) In rats CSF Vomiting role
bacterial cell penetration QTc prolongation
wall noted.
D3: Bacteriostatic 8–12 g per day divided 2–3 Oral Poor GI intolerance No definite
Para- times per day Hepatotoxicity role
aminosalycylic Children: 200-300 mg/Kg/ Hypothyroidism
acid day
D3: In vitro activity 1000 mg BD IV or IM Good Nausea No definite
Imipenem– Vomiting role
cilastatin Diarrhoea
combined with seizures
clavulanic acid
D3: In vitro activity 1000 mg TDS IV Good Nausea No definite
Meropenem Children: 40 mg/Kg/dose Vomiting role
TDS Diarrhoea No definite
seizures role
D3: Limited data 80 mg/kg/day in 2 divided Oral or IV Poor Diarrhoea and GI No definite
Amoxicillin- doses intolerance role
clavulanate
BD: twice a day; CSF: cerebrospinal fluid; DR-TBM: drug-resistant tuberculous meningitis; GI: gastro-intestinal; IV: intravenous; IM: intramuscular; MDR: multidrug-
resistant; OD: once in a day; TDS: thrice a day.
828 R. K. GARG ET AL.
penetration. Existing drugs (like linezolid, clofazimine, and
meropenem clavulanate) should also be repurposed to tap
their full potential for the treatment of drug-resistant
tuberculous meningitis as well [124]. Newer regimens
with higher doses of first-line drugs also need to be
assessed. Intensified antituberculosis treatment regimen
with higher-dose rifampin might be an effective option
against isoniazid mono-resistant tuberculous meningitis.
No second-line anti-tuberculosis drug regimen has been
tested in a randomized controlled fashion so far. Four or
five second-line drugs with adequate CSF penetration need
to be compared with currently used regimens. Certain
nonsteroidal anti-inflammatory drugs (NSAIDs) have been
used against M. tuberculosis [125,126]. In addition, NSAIDs
are potentially useful in controlling enhanced inflammatory
responses (presenting as a paradoxical reaction), although
no evidence is currently available [102]. Adding aspirin to
antituberculosis drugs and corticosteroids regimen may
help in reducing the risk of strokes, severe disabilities,
and deaths[127].
15. Five-year view
End TB strategy, adopted by the World Health Assembly in
2014, focuses on ending the global tuberculosis epidemic.
There are four important components of End TB Strategy:
(A) early diagnosis and universal drug susceptibility testing,
and monitoring of contacts and high-risk groups; (B) treat-
ment and support to all patients; (C) collaborating tuber-
culosis and HIV cases; and (D) preventive treatment of
high-risk individuals and vaccination. It has been envi-
saged that End TB strategy will help in eliminating all
kinds of tuberculosis, including drug-resistant tuberculous
meningitis, by year 2035 [128].
Key issues
● Drug-resistant tuberculous meningitis has a global presence
and is mostly reported from high tuberculosis burden
countries.
● Both multidrug-resistant and isoniazid mono-resistant
tuberculous meningitis are associated with high mortality.
● In some cases, even extensively drug-resistant mycobacter-
ial strains have caused meningitis.
● HIV-infected patients are more prone to drug-resistant
tuberculous meningitis.
● Drug-resistant tuberculous meningitis is usually a dissemi-
nated disease, and lungs and lymph nodes are likely to be
concomitantly affected.
● Xpert MTB/RIF Ultra assay is a next-generation Xpert® MTB/
RIF assay technology that can detect M. tuberculosis even in
specimens with low numbers of bacilli.
● Treatment of drug-resistant tuberculous meningitis is done
on the lines of recommended treatment for multidrug-
resistant pulmonary tuberculosis.
● Antituberculosis drugs with good CSF penetration are
preferred.
● The optimum drug regimen is unknown as no second-line
antituberculosis drug-containing regimen has been tested
in a randomized controlled fashion.
● A combination of levofloxacin, kanamycin, ethionamide,
linezolid, and pyrazinamide would be an appropriate
regimen for multidrug-resistant tuberculous meningitis.
● End TB strategy might address the serious problem of drug-
resistant tuberculous meningitis as well.
Funding
The manuscript was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
Funding
The manuscript was not funded.
References
Papers of special note have been highlighted as either of interest (•)
or of considerable interest (••) to readers.
1. World Health Organization. 2016. World Health Organization treat-
ment guidelines for drug-resistant tuberculosis. [cited 2018 Feb 2].
Avialable from: http://apps.who.int/iris/bitstream/10665/250125/1/
9789241549639-eng.pdf
2. World Health Organization. Tuberculosis. fact sheet. reviewed.
[updated 2018 Jan; cited 2018 Feb 2]. Avialable from: http://www.
who.int/mediacentre/factsheets/fs104/en/Assessed
3. Vinnard C, King L, Munsiff S, et al. Long-term mortality of patients
with tuberculous meningitis in New York City: a cohort study. Clin
Infect Dis. 2017;15(64):401–407.
•• Isoniazid resistance adversely affects the outcome in tubercu-
lous meningitis.
4. Wang T, Feng G-D, Pang Y, et al. High rate of drug resistance
among tuberculous meningitis cases in Shaanxi province, China.
Sci Rep. 2016;6:25251.
5. Kaviyil JE, Ravikumar R. Diagnosis of tuberculous meningitis: cur-
rent scenario from A tertiary neurocare centre In India. Indian J
Tuberc. 2017;64:183–188.
6. Caws M, Thwaites GE, Duy PM, et al. Molecular analysis of
Mycobacterium tuberculosis causing multidrug-resistant tubercu-
losis meningitis. Int J Tuberc Lung Dis. 2007;11:202–208.
7. Vinnard C, Winston CA, Wileyto EP, et al. Isoniazid-resistant tuber-
culous meningitis, United States, 1993-2005. Emerg Infect Dis.
2011;17:539–542.

8. Thwaites GE, Chau TTH, Caws M, et al. Isoniazid resistance, myco-
bacterial genotype and outcome in Vietnamese adults with tuber-
culous meningitis. Int J Tuberc Lung Dis. 2002;6:865–871.
9. Gupta R, Kushwaha S, Thakur R, et al. Predictors of adverse out-
come in patients of tuberculous meningitis in a multi-centric study
from India. Indian J Tuberc. 2017;64:296–301.
10. Kambli P, Nikam C, Shetty A, et al. Multi-drug resistant tuberculous
meningitis. Indian J Med Microbiol. 2016;34:255.
11. Senbayrak S, Ozkutuk N, Erdem H, et al. Antituberculosis drug
resistance patterns in adults with tuberculous meningitis:
results of haydarpasa-iv study. Ann Clin Microbiol Antimicrob.
2015;14:47.
12. Sharma K, Modi M, Kaur H, et al. rpoB gene high-resolution melt
curve analysis: a rapid approach for diagnosis and screening of
drug resistance in tuberculous meningitis. Diagn Microbial Infect
Dis. 2015;83:144–149.
13. Nhu NTQ, Heemskerk D, Thu DDA, et al. Evaluation of GeneXpert
MTB/RIF for diagnosis of tuberculous meningitis. J Clin Microbiol.
2014;52:226–233.
14. Jain A, Dixit P, Jaiswal I, et al. Drug resistance in mycobacterial
isolates from meningitis cases. Pediatr Infect Dis J. 2012;31:1317.
15. Seddon JA, Visser DH, Bartens M, et al. Impact of drug resistance on
clinical outcome in children with tuberculous meningitis. Pediatr
Infect Dis J. 2012;31:711–716.
16. Duo L, Ying B, Song X, et al. Molecular profile of drug resistance in
tuberculous meningitis from southwest china. Clin Infect Dis.
2011;53:1067–1073.
17. Vinnard C, Winston CA, Wileyto EP, et al. Multidrug resistant tuber-
culous meningitis in the United States, 1993-2005. J Infect.
2011;63:240–242.
18. Yorsangsukkamol J, Chaiprasert A, Prammananan T, et al. Molecular
analysis of Mycobacterium tuberculosis from tuberculous meningi-
tis patients in Thailand. Tuberculosis. 2009;89:304–309.
19. Nagarathna S, Rafi W, Veenakumari HB, et al. Drug susceptibility profil-
ing of tuberculous meningitis. Int J Tuberc Lung Dis. 2008;12:105–107.
20. Cecchini D, Ambrosioni J, Brezzo C, et al. Tuberculous meningitis in
HIV-infected patients: drug susceptibility and clinical outcome.
AIDS. 2007;21:373–374.
21. Sharma D, Shah I, Patel S. Late onset hydrocephalus in children
with tuberculous meningitis. J Fam Med Prim Care. 2016;5:873–874.
22. Yoo KM, Joo E-J, Yeom J-S, et al. Dissemination of multidrug-
resistant tuberculosis in a patient with acute HIV infection. BMC
Infect Dis. 2014;14:462.
23. Sharma B, Handa R, Nagpal K, et al. Cycloserine-induced psychosis
in a young female with drug-resistant tuberculosis. Gen Hosp
Psychiatry. 2014;36(451):e3–4.
24. Bernard C, Brossier F, Fréchet-Jachym M, et al. Concomitant multi-
drug-resistant pulmonary tuberculosis and susceptible tuberculous
meningitis. Emerg Infect Dis. 2014;20:506–507.
25. Mauro MV, Cavalcanti P, Ledonne R, et al. Description of primary
multidrug-resistant tuberculous meningitis in an Italian child.
Microb Drug Resist. 2012;18:71–73.
26. Ikegame S, Wakamatsu K, Fujita M, et al. A case of isoniazid-
resistant miliary tuberculosis in which tuberculous meningitis para-
doxically developed despite systemic improvement. J Infect
Chemother. 2011;17:689–693.
27. Marschall J, Evison J-M, Droz S, et al. Disseminated tuberculosis
following total knee arthroplasty in an HIV patient. Infection.
2008;36:274–278.
28. Kohli A, Kapoor R. Neurological picture embolic spread of tubercu-
lomas in the brain in multidrug resistant tubercular meningitis. J
Neurol Neurosurg Psychiatry. 2008;79:198.
29. Meybeck A, Calbet J, Ruimy R, et al. Multidrug-resistant tuberculous
meningitis in an HIV-positive patient: a challenging disease. AIDS
Patient Care STDs. 2007;21:149–153.
30. Ersoy Y, Ates O, Onal C, et al. Cerebellar abscess and syringomyelia
due to isoniazid-resistant Mycobacterium tuberculosis. J Clin
Neurosci. 2007;14:86–89.
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 829
31. Ripamonti D, Barbò R, Rizzi M, et al. New times for an old disease:
intracranial mass lesions caused by Mycobacterium tuberculosis in
5 HIV-negative African immigrants. Clin Infect Dis. 2004;39:e35–45.
32. Daikos GL, Cleary T, Rodriguez A, et al. Multidrug-resistant tuber-
culous meningitis in patients with AIDS. Int J Tuberc Lung Dis.
2003;7:394–398.
33. Sofia M, Maniscalco M, Honoré N, et al. Familial outbreak of dis-
seminated multidrug-resistant tuberculosis and meningitis. Int J
Tuberc Lung Dis. 2001;5:551–558.
34. Silber E, Sonnenberg P, Saffer D, et al. Multidrug-resistant tubercu-
lous meningitis in a health care worker. Int J Tuberc Lung Dis.
1998;2:774.
35. Horn DL, Hewlett D, Peterson S, et al. RISE-resistant tuberculous
meningitis in AIDS patient. Lancet. 1993;341:177–178.
36. Rich AR, McCordock HA. The pathogenesis of tuberculous menin-
gitis. Bull Johns Hopkins Hosp. 1933;52:5–37.
37. Donald PR, Schaaf HS, Schoeman JF. Tuberculous meningitis and
miliary tuberculosis: the Rich focus revisited. J Infect. 2005;50:193–
195.
38. van Leeuwen LM, Boot M, Kuijl C, et al. Mycobacteria employ two
different mechanisms to cross the blood-brain barrier. Cell
Microbiol. 2018 May;10:e12858.
39. Dastur DK, Manghani DK, Udani PM. Pathology and pathogenetic
mechanisms in neurotuberculosis. Radiol Clin North Am.
1995;33:733–752.
40. Dastur DK, Lalitha VS, Udani PM, et al. The brain and meninges in
tuberculous meningitis-gross pathology in 100 cases and patho-
genesis. Neurol India. 1970;18:86–100.
41. Zhang J, Hu X, Hu X, et al. Clinical features, outcomes and mole-
cular profiles of drug resistance in tuberculous meningitis in non-
HIV patients. Sci Rep. 2016;6:19072.
42. Crump JA, Reller LB. Two decades of disseminated tuberculosis at a
university medical center: the expanding role of mycobacterial
blood culture. Clin Infect Dis. 2003;37:1037–1043.
43. Solomons RS, Goussard P, Visser DH, et al. Chest radiograph find-
ings in children with tuberculous meningitis. Int J Tuberc Lung Dis.
2015;19:200–204.
44. Miftode EG, Dorneanu OS, Leca DA, et al. Tuberculous meningitis in
children and adults: a 10-year retrospective comparative analysis.
PLoS One. 2015;10:e0133477.
45. Riste M, Hobden D, Pollard C, et al. Diagnosis of tuberculous
meningitis with invasive pulmonary sampling. Lancet Infect Dis.
2018;18:25–26.
46. Thwaites GE, Chau TT, Stepniewska K, et al. Diagnosis of adult
tuberculous meningitis by use of clinical and laboratory features.
Lancet. 2002;360:1287–1292.
47. Sharma P, Garg RK, Verma R, et al. Incidence, predictors and prog-
nostic value of cranial nerve involvement in patients with tubercu-
lous meningitis: a retrospective evaluation. Eur J Intern Med.
2011;22:289–295.
48. Sinha MK, Garg RK, Anuradha H, et al. Vision impairment in tuber-
culous meningitis: predictors and prognosis. J Neurol Sci.
2010;290:27–32.
49. Tai MS, Viswanathan S, Rahmat K, et al. Cerebral infarction pattern
in tuberculous meningitis. Sci Rep. 2016;6:38802.
50. Gupta R, Garg RK, Jain A, et al. Spinal cord and spinal nerve root
involvement (myeloradiculopathy) in tuberculous meningitis.
Medicine (Baltimore). 2015;94:e404.
51. Kumar K, Giribhattanavar P, Chandrashekar N, et al. Correlation of
clinical, laboratory and drug susceptibility profiles in 176 patients
with culture positive TBM in a tertiary neurocare centre. Diagn
Microbiol Infect Dis. 2016;86:372–376.
52. Thwaites GE, Lan NTN, Dung NH, et al. Effect of antituberculosis
drug resistance on response to treatment and outcome in adults
with tuberculous meningitis. J Infect Dis. 2005;192:79–88.
53. Padayatchi N, Bamber S, Dawood H, et al. Multidrug-resistant
tuberculous meningitis in children in durban, South Africa.
Pediatr Infect Dis J. 2006;25:147–150.
830 R. K. GARG ET AL.
54. Patel VB, Padayatchi N, Bhigjee AI, et al. Multidrug-resistant tuber-
culous meningitis in KwaZulu-Natal, South Africa. Clin Infect Dis.
2004;38:851–856.
55. Kaplan SR, Topal J, Sosa L, et al. A patient with central nervous
system tuberculomas and a history of disseminated multi-drug-
resistant tuberculosis. Journal of Clinical Tuberculosis and Other
Mycobacterial Diseases. 2018;10:9–16.
56. Watt G, Selkon JB, Bautista S, et al. Drug resistant tuberculous
meningitis in the Philippines: report of a case. Tubercle
1989;70:139–141.
57. Rohlwink UK, Donald K, Gavine B, et al. Clinical characteristics and
neurodevelopmental outcomes of children with tuberculous
meningitis and hydrocephalus. Dev Med Child Neurol.
2016;58:461–468.
58. Güneş A, UlucÜ U, Aktar F, et al. Clinical, radiological and laboratory
findings in 185 children with tuberculous meningitis at a single
centre and relationship with the stage of the disease. Ital J Pediatr.
2015;41:75.
59. British Medical Research Council. Streptomycin treatment of tuber-
culous meningitis. BMJ. 1948;1:582–597.
60. Abdelmalek R, Kanoun F, Kilani B, et al. Tuberculous meningitis in
adults: MRI contribution to the diagnosis in 29 patients. Int J Infect
Dis. 2006;10:372–377.
61. Garg RK, Malhotra HS, Jain A. Neuroimaging in tuberculous menin-
gitis. Neurol India. 2016;64:219–227.
62. Singh AK, Malhotra HS, Garg RK, et al. Paradoxical reaction in
tuberculous meningitis: presentation, predictors and impact on
prognosis. BMC Infect Dis. 2016;16:306.
63. Marais S, Lai RPJ, Wilkinson KA, et al. Inflammasome activation
underlying central nervous system deterioration in HIV-associated
tuberculosis. J Infect Dis. 2017;21:677–686.
64. Gonzales Zamora JA, Espinoza LA, Nwanyanwu RN. Neurosyphilis
with concomitant cryptococcal and tuberculous meningitis in a
patient with AIDS: report of a unique case. Case Rep Infect Dis.
2017;2017:4103858.
65. Fang W, Zhang L, Liu J, et al. Tuberculosis/cryptococcosis co-infec-
tion in China between 1965 and 2016. Emerg Microbes Infect.
2017;6:e73.
66. Sonneville R, Magalhaes E, Meyfroidt G. Central nervous system
infections in immunocompromised patients. Curr Opin Crit Care.
2017;23:128–133.
67. Ahn S, Lim KS. Three cases of neoplastic meningitis initially diag-
nosed with infectious meningitis in emergency department. Case
Rep Emerg Med. 2013;2013:561475.
68. Taylor G, Karlin N, Halfdanarson TR, et al. Leptomeningeal carcino-
matosis in colorectal cancer: the mayo clinic experience. Clin
Colorectal Cancer. 2018;17:e183–e187.
69. Ko MW, Turkeltaub PE, Lee EB, et al. Primary diffuse leptomeningeal
gliomatosis mimicking a chronic inflammatory meningitis. J Neurol
Sci. 2009;278:127–131.
70. Chaidir L, Annisa J, Dian S, et al. Microbiological diagnosis of adult
tuberculous meningitis in a ten-year cohort in Indonesia. Diagn
Microbiol Infect Dis. 2018;91:42–46.
71. Al-Mutairi NM, Ahmad S, Mokaddas E. Molecular screening versus
phenotypic susceptibility testing of multidrug-resistant
Mycobacterium tuberculosis isolates for streptomycin and etham-
butol. Microb Drug Resist. 2018. Epub ahead of print. DOI:10.1089/
mdr.2017.0294.
72. Bastos ML, Hussain H, Weyer K, et al. Treatment outcomes of
patients with multidrug-resistant and extensively drug-resistant
tuberculosis according to drug susceptibility testing to first- and
second-line drugs: an individual patient data meta-analysis. Clin
Infect Dis. 2014;59:1364–1374.
73. Seung KJ, Keshavjee S, Rich ML. Multidrug-resistant tuberculosis
and extensively drug-resistant tuberculosis. Cold Spring Harb
Perspect Med. 2015;5:a017863.
74. Brosch R, Gordon SV, Marmiesse M, et al. A new evolutionary
scenario for the Mycobacterium tuberculosis complex. Proc Natl
Acad Sci U S A. 2002;9:3684–3689.
75. Gupta R, Thakur R, Gupta P, et al. Evaluation of geno type
mtbdrplus line probe assay for early detection of drug resistance
in tuberculous meningitis patients in India. J Glob Infect Dis.
2015;7:5–10.
76. Bahr NC, Tugume L, Rajasingham R, et al. Improved diagnostic
®
sensitivity for tuberculous meningitis with Xpert( ) MTB/RIF of
centrifuged CSF. Int J Tuberc Lung. 2015;19:1209–1215.
77. Bahr NC, Marais S, Caws M, et al. GeneXpert MTB/Rif to diagnose
tuberculous meningitis: perhaps the first test but not the last. Clin
Infect Dis. 2016;62:1133–1135.
78. World Health Organization. Next-generation Xpert MTB/RIF ®
Ultra assay recommended by WHO. [cited 2018 Feb 2].
Avialable from: http://www.who.int/tb/features_archive/Xpert-
Ultra/en/assessed
79. Bahr NC, Nuwagira E, Evans EE, et al. Diagnostic accuracy of Xpert
MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a
prospective cohort study. Lancet Infect Dis. 2018;18:68–75.
• Usage of Xpert MTB/RIF Ultra in the diagnostics of tuberculous
meningitis needs to be explored further in the field setting,
data are currently limited.
80. Chin JH. Xpert MTB/RIF Ultra: the long-awaited game changer for
tuberculous meningitis? Eur Respir J. 2017;50(4): 1701201. pii.
®
81. Theron G, Peter J, Richardson M, et al. GenoType MTBDRsl assay
for resistance to second-line anti-tuberculosis drugs. Cochrane
Database Syst Rev. 2016;9:CD010705.
82. Xie YL, Chakravorty S, Armstrong DT, et al. Evaluation of a rapid
molecular drug-susceptibility test for tuberculosis. N Engl J Med.
2017;377:1043–1054.
83. World Health Organization. Guidelines for treatment of drug-sus-
ceptible tuberculosis and patient care (2017 update). [cited 2018
Feb 2]. Avialable from: http://apps.who.int/iris/bitstream/10665/
255052/1/9789241550000-eng.pdf?ua=1
84. Akkerman OW, Odish OFF, Bolhuis MS, et al. Pharmacokinetics of
bedaquiline in cerebrospinal fluid and serum in multidrug-resistant
tuberculous meningitis. Clin Infect Dis. 2016;62:523–524.
85. Van Toi P, Pouplin T, Tho NDK, et al. High-performance liquid
chromatography with time-programmed fluorescence detection
for the quantification of Levofloxacin in human plasma and cere-
brospinal fluid in adults with tuberculous meningitis. J Chromatogr
B Analyt Technol Biomed Life Sci. 2017;1061–1062:256–262.
86. Kalita J, Bhoi SK, Betai S, et al. Safety and efficacy of additional
levofloxacin in tuberculous meningitis: a randomized controlled
pilot study. Tuberculosis. 2016;98:1–6.
87. Alffenaar JWC, van Altena R, Bökkerink HJ, et al. Pharmacokinetics
of moxifloxacin in cerebrospinal fluid and plasma in patients with
tuberculous meningitis. Clin Infect Dis. 2009;49:1080–1082.
88. Donald PR. Cerebrospinal fluid concentrations of antituberculosis
agents in adults and children. Tuberculosis. 2010;90:279–292.
89. Goff DC, Henderson DC, Evins AE, et al. A placebo-controlled cross-
over trial of D-cycloserine added to clozapine in patients with
schizophrenia. Biol Psychiatry. 1999;45:512–514.
90. Tsona A, Metallidis S, Foroglou N, et al. Linezolid penetration into
cerebrospinal fluid and brain tissue. J Chemother. 2010;22:17–19.
91. Holdiness MR. Clinical pharmacokinetics of clofazimine. A review.
Clin Pharmacokinet. 1989;16:74–85.
92. Phuapradit P, Supmonchai K, Kaojarern S, et al. The blood/cere-
brospinal fluid partitioning of pyrazinamide: a study during the
course of treatment of tuberculous meningitis. J Neurol
Neurosurg Psychiatry. 1990;53:81–82.
93. Ellard GA, Humphries MJ, Gabriel M, et al. Penetration of pyrazina-
mide into the cerebrospinal fluid in tuberculous meningitis. Br Med
J Clin Res Ed. 1987;294:284–285.
94. Seifert M, Georghiou SB, Garfein RS, et al. Impact of fluoroquino-
lone use on mortality among a cohort of patients with suspected
drug-resistant tuberculosis. Clin Infect Dis. 2017;65:772–778.
95. Te Brake L, Dian S, Ganiem AR, et al. Pharmacokinetic/pharmaco-
dynamic analysis of an intensified regimen containing rifampicin
and moxifloxacin for tuberculous meningitis. Int J Antimicrob
Agents. 2015;(45):496–503.

96. Heemskerk AD, Bang ND, Mai NTH, et al. Intensified antituberculo-
sis therapy in adults with tuberculous meningitis. N Engl J Med.
2016;374:124–134.
•• Intensified antituberculosis treatment regimen failed to pro-
vide any extra benefit over convention treatment regimen.
97. Mamatha HG, Shanthi V. Baseline resistance and cross-resistance
among fluoroquinolones in multidrug-resistant Mycobacterium
tuberculosis isolates at a national reference laboratory in India. J
Glob Antimicrob Resist. 2017;12:5–10.
98. Berning SE, Cherry TA, Iseman MD. Novel treatment of meningitis
caused by multidrug-resistant Mycobacterium tuberculosis with
intrathecal levofloxacin and amikacin: case report. Clin Infect Dis.
2001;32:643–646.
99. Kass JS, Shandera WX. Nervous system effects of antituberculosis
therapy. CNS Drugs. 2010;24:655–667.
100. Alsleben N, Garcia-Prats AJ, Hesseling AC, et al. Successful treat-
ment of a child with extensively drug-resistant tuberculous menin-
gitis. J Pediatr Infect Dis Soc. 2015;4:e41–44.
101. van Toorn R, Schaaf HS, Laubscher JA, et al. Short intensified treatment
in children with drug-susceptible tuberculous meningitis. Pediatr Infect
Dis J. 2014;33:248–252.
• Short intensified antituberculous treatment is used in South Africa
but no randomised control trial indicating its efficacy exists.
102. Li H, Lu J, Liu J, et al. Linezolid is associated with improved early
outcomes of childhood tuberculous meningitis. Pediatr Infect Dis J.
2016;35:607–610.
103. Sun F, Ruan Q, Wang J, et al. Linezolid manifests a rapid and dramatic
therapeutic effect for patients with life-threatening tuberculous menin-
gitis. Antimicrob Agents Chemother. 2014;58:6297–6301.
• Linezolid is the drug that needs to be explored further in the
management of tuberculous meningitis, particularly, drug-
resistant tuberculous meningitis.
104. Srivastava A, Kshetrimayum S, Gupta SK, et al. Linezolid-induced
optic neuropathy in XDR pulmonary TB: a case series. Indian J
Tuberc. 2017;64:129–133.
105. Mehta S, Das M, Laxmeshwar C, et al. Linezolid-associated optic
neuropathy in drug-resistant tuberculosis patients in Mumbai,
India. PloS One. 2016;11:e0162138.
106. Shibata M, Shimokawa Y, Sasahara K, et al. Absorption, distribu-
tion and excretion of the anti-tuberculosis drug delamanid in
rats: extensive tissue distribution suggests potential therapeutic
value for extrapulmonary tuberculosis. Biopharm Drug Dispos.
2017;38:301–312.
107. Sutter R, Rüegg S, Tschudin-Sutter S. Seizures as adverse events of
antibiotic drugs: a systematic review. Neurology. 2015;85:1332–1341.
108. Donald PR. Chemotherapy for tuberculous meningitis. N Engl J
Med. 2016;374:179–181.
109. Allana S, Shashkina E, Mathema B, et al. pnca gene mutations
associated with pyrazinamide resistance in drug-resistant tubercu-
losis, South Africa and Georgia. Emerg Infect Dis. 2017;23:491–495.
110. Gegia M, Winters N, Benedetti A, et al. Treatment of isoniazid-
resistant tuberculosis with first-line drugs: a systematic review
and meta-analysis. Lancet Infect Dis. 2017;17:223–234.
•• This meta-analysis observed that the treatment of isoniazid-
resistant tuberculosis with first-line antituberculosis drugs
results in suboptimal outcomes.
111. Vinnard C, Winston CA, Wileyto EP, et al. Isoniazid resistance and
death in patients with tuberculous meningitis: retrospective cohort
study. BMJ. 2010;341:c4451.
112. Cresswell FV, Ssebambulidde K, Grint D, et al. High dose oral and
intravenous rifampicin for improved survival from adult tubercu-
lous meningitis: a phase II open-label randomised controlled trial
(the RifT study) [version 1; referees: 1 approved]. Wellcome Open
Res. 2018;3:83.
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 831
113. Prasad K, Singh MB, Ryan H. Corticosteroids for managing tubercu-
lous meningitis. Cochrane Database Syst Rev. 2016;4:CD002244.
114. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the
treatment of tuberculous meningitis in adolescents and adults. N
Engl J Med. 2004;351:1741–1751.
•• This was the study that established that treatment with dex-
amethasone in tuberculous meningitis improves survival in
adult patients. In this large study many drug-resistant tuber-
culous meningitis patients were included.
115. Wells CD, Cegielski JP, Nelson LJ, et al. HIV infection and multidrug-
resistant tuberculosis: the perfect storm. J Infect Dis. 2007;196
(Suppl 1):S86–107.
• HIV infection and multidrug-resistant tuberculous meningitis
is a deadly combination
116. Podlekareva DN, Efsen AM, Schultze A, et al. Tuberculosis-related
mortality in people living with HIV in Europe and Latin America: an
international cohort study. Lancet HIV. 2016;3:e120–31.
117. Thwaites GE, Duc Bang N, Huy Dung N, et al.. The influence of HIV
infection on clinical presentation, response to treatment, and out-
come in adults with Tuberculous meningitis. J Infect Dis.
2005;192:2134–2141.
118. Torok ME, Chau TTH, Mai PP, et al. Clinical and microbiological
features of HIV-associated tuberculous meningitis in Vietnamese
adults. PloS One. 2008;3:e1772.
119. Fischl MA, Daikos GL, Uttamchandani RB, et al. Clinical presentation and
outcome of patients with HIV infection and tuberculosis caused by
multiple-drug-resistant bacilli. Ann Intern Med. 1992;117:184–190.
120. Tho DQ, Török ME, Yen NTB, et al. Influence of antituberculosis
drug resistance and Mycobacterium tuberculosis lineage on out-
come in HIV-associated tuberculous meningitis. Antimicrob Agents
Chemother. 2012;56:3074–3079.
121. Günthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for
treatment and prevention of HIV infection in adults: 2016 recom-
mendations of the international antiviral society-USA panel. JAMA.
2016;316:191–210.
122. Török ME, Yen NTB, Chau TTH, et al. Timing of initiation of
antiretroviral therapy in human immunodeficiency virus (HIV)–
associated tuberculous meningitis. Clin Infect Dis.
2011;52:1374–1383.
•• Thisrandomized study suggested that antiretroviral therapy in
human immunodeficiency virus–associated tuberculous
meningitis should be deferred for 6-8 weeks as adverse events
are more if treatment is started early.
123. Heemskerk AD, Nguyen MTH, Dang HTM, et al. Clinical outcomes of
patients with drug-resistant tuberculous meningitis treated with an
intensified antituberculosis regimen. Clin Infect Dis. 2017;65:20–28.
•• Intensified antituberculosis treatment takes care of isoniazid
resistant tuberculous meningitis cases, but in multidrug-resis-
tant tuberculous meningitis situation remains grim.
124. Harausz EP, Garcia-Prats AJ, Seddon JA, et al. New and repurposed
drugs for pediatric multidrug-resistant tuberculosis Practice-Based
Recommendations. Am J Respir Crit Care Med. 2017;195:1300–1310.
125. Maitra A, Bates S, Shaik M, et al. Repurposing drugs for treatment
of tuberculosis: a role for non-steroidal anti-inflammatory drugs. Br
Med Bull. 2016;118:138–148.
126. Ivanyi J, Zumla A. Nonsteroidal antiinflammatory drugs for adjunc-
tive tuberculosis treatment. J Infect Dis. 2013;208:185–188.
127. Mai NT, Dobbs N, Phu NH, et al. A randomised double blind
placebocontrolled phase 2 trial of adjunctive aspirin for tubercu-
lous meningitis in HIV-uninfected adults. Elife. 2018;7:e33478, pii.
128. World Health Organization. WHO end tb strategy. Global strategy
and targets for tuberculosis prevention, care and control after
2015. [cited 2018 Feb 2]. Avialable from: http://apps.who.int/iris/
bitstream/10665/250125/1/9789241549639-eng.pdf