J Antimicrob Chemother 2014; 69: 2246 – 2251

doi:10.1093/jac/dku103 Advance Access publication 20 April 2014

Safety and efficacy of levofloxacin versus rifampicin in tuberculous

meningitis: an open-label randomized controlled trial
J. Kalita, U. K. Misra*, S. Prasad and S. K. Bhoi

Department of Neurology, Sanjay Gandhi Post Graduate Medical Sciences, Lucknow, India

*Corresponding author. Tel: +91-522-2494167; Fax: +91-522-2668811; E-mail: drukmisra@rediffmail.com or ukmisra@sgpgi.ac.in

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Received 12 December 2013; returned 4 February 2014; revised 7 March 2014; accepted 15 March 2014

Objectives: We report the efficacy and safety of levofloxacin versus rifampicin in tuberculous meningitis (TBM).
Patients and methods: In this open-label, randomized controlled trial from India, patients with TBM diagnosed
on the basis of clinical, MRI and CSF findings were included. Patients with hepatic or renal dysfunction, organ
transplantation, malignancy, pregnancy, lactation, allergy, seizure, age ,15 years and antitubercular treatment
≥1 month were excluded. Sixty patients each were randomized to levofloxacin (10 mg/kg, maximum 500 mg) or
rifampicin (10 mg/kg, maximum 450 mg). They also received isoniazid, pyrazinamide, ethambutol, prednisolone
and aspirin. The primary outcome was death and secondary outcome measures were 6 month disability, repeat
MRI changes and serious adverse events (SAEs).
Results: The median age of the patients was 34.5 (16 – 75) years. The baseline clinical and MRI findings were
similar between the two groups. At 6 months, 13 out of 60 (21.7%) patients in the levofloxacin arm and 23
out of 60 (38.3%) patients in the rifampicin arm had died (P ¼ 0.07). On Cox regression analysis, survival in the
levofloxacin group was significantly better than in the rifampicin group (hazard ratio 2.13, 95% CI 1.04 – 4.34,
P ¼ 0.04). The functional outcome (P ¼ 0.47) was, however, not significantly different between the two groups.
On intention-to-treat analysis, 10 out of 47 (21.3%) in the levofloxacin arm and 5 out of 37 (13.5%) in the rifam-
picin arm had poor recovery. Repeat MRI findings did not differ between the groups. Levofloxacin was discontin-
ued more frequently than rifampicin due to SAEs (16 versus 4, P¼ 0.01).
Conclusions: Levofloxacin is superior to rifampicin in reducing 6 month death in TBM but not disability.
Levofloxacin may be used in TBM especially in those patients with hepatotoxicity and without seizure.

Keywords: MRI, prognosis, antitubercular drugs, corticosteroids

Introduction
Tuberculous meningitis (TBM) occurs in 10% of patients with
tuberculosis.1 It results in death or severe disability in nearly
half of affected patients.2 The introduction of rifampicin and
pyrazinamide has not resulted in further decline of mortality
over isoniazid and streptomycin.3,4 Rifampicin is bactericidal but
has poor CSF penetration.5 The concentration of rifampicin has
been found to be below the MIC in two studies.6,7 The use of rifam-
picin in TBM is based on a few trials that are not class I.8,9 The role
of rifampicin in the treatment of TBM was highlighted in a study in
which all patients resistant to isoniazid and rifampicin died, but
only 28.7% died who were susceptible to antitubercular drugs.10
In a recent study, 450 mg of rifampicin orally resulted in a CSF
concentration below the assay level (0.26 mg/L) in 64% of
patients, whereas 600 mg of rifampicin intravenously resulted in
a higher CSF concentration and only 4% were below the assay
level. The higher dose of rifampicin in that study was associated
with lower 6 month mortality without significant increase in
hepatotoxicity.11
Besides the CSF penetration and efficacy of antitubercular
drugs, the safety profile of the drug is also important. Drug-
induced hepatitis is more common in Asians and has been
reported in 26% –36% of patients.12,13 Of the first-line antituber-
cular drugs, isoniazid, pyrazinamide and rifampicin have hepato-
toxic potential. In view of poor CSF penetration, hepatotoxicity
and a paucity of strong evidence for the benefit of a standard
dose of rifampicin in TBM, it is important to explore other antitu-
bercular drugs. Of the candidate drugs, clarithromycin and fluor-
oquinolones have been tried in tuberculosis. The latter are more
promising. Quinolones are bactericidal, have no hepatotoxicity
and have been reported to be beneficial in multidrug-resistant
tuberculosis.14 Moxifloxacin and levofloxacin have higher CSF pene-
tration compared with other quinolones and have been evaluated

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2246
Levofloxacin versus rifampicin in tuberculous meningitis
in a few studies as an add-on or alternative to ethambutol.10,11 In
the present study, we therefore report the efficacy and safety of
levofloxacin compared with rifampicin in patients with TBM.
Methods
Study design
This is an investigator-initiated, single-centre, open-label randomized con-
trolled trial comparing the efficacy and safety of levofloxacin versus rifam-
picin in patients with TBM in addition to isoniazid, pyrazinamide and
ethambutol. The study was conducted in a tertiary care teaching hospital
in India. The protocol was designed by the first and second authors.
Consecutive TBM patients admitted to the neurology service were enrolled
from July 2009 to June 2012. The study was approved by the Local Ethics
Committee (no. A-15:PGI/DM/IEC/50/13.4.2010) and was retrospectively
registered in the Clinical Trial Registry, India (CTRI/2012/11/003155). The
patients or their representatives gave informed consent. The sample size
was calculated keeping the type I error a ¼0.05 and type II error b¼0.15
using Fisher’s exact test. We considered the absolute reduction in deaths in
the levofloxacin arm as 15%. Death in the rifampicin arm was considered
to be 40% based on the reported mortality in TBM.15,16 The required sam-
ple size was 64 in each arm.
Inclusion criteria
Patients with TBM were diagnosed on the basis of clinical, MRI and CSF
findings. Essential criteria included the presence of meningitis symptoms
consisting of fever, headache or vomiting for ≥2 weeks in patients in
whom malaria, septic and fungal meningitis were excluded. Supportive cri-
teria included the following: (i) CSF cells ≥0.2×109/L with lymphocytic pre-
dominance, protein .1 g/L, sterile bacterial and fungal culture and
absence of cryptococcal antigen; (ii) MRI evidence of exudates, hydroceph-
alus, infarction or tuberculoma; and (iii) extra-CNS tuberculosis.
The presence of essential criteria and any two of the supportive criteria
was considered as TBM. The presence of acid-fast bacilli (AFB) in the CSF
smear or culture, positive PCR or IgM antibody in the CSF was considered
as definite TBM.17
Exclusion criteria
Patients with seizures, liver or kidney failure, malignancy, long-standing
immunosuppressive therapy, organ transplantation, pregnancy, lactation,
age ,15 years and prior antitubercular treatment (ATT) for ≥1 month
were excluded.
Evaluation
Patients were subjected to detailed clinical evaluation. The duration of ill-
ness, presence of focal neurological deficit, seizure, evidence of raised
intracranial pressure (hyperventilation and extensor posturing) and evi-
dence of extra-CNS tuberculosis (lymph node, lungs, abdomen and bone
and joint) were noted. Consciousness was assessed by the Glasgow Coma
Scale (GCS). The presence of cranial nerve palsy was noted. Focal weakness
was categorized into monoplegia, hemiplegia, paraplegia or quadriplegia.
The meningitis was graded as follows: stage I, meningitis only; stage II,
meningitis with focal neurological deficit or GCS score 11 – 14; or stage
III, meningitis with GCS score ,11.18
Investigations
Blood counts, erythrocyte sedimentation rate, haemoglobin, blood sugar,
serum creatinine, albumin, bilirubin, transaminase and electrolytes were
measured at admission and were repeated when required. Radiograph
of the chest, electrocardiogram and HIV serology were performed in all
patients. Cranial MRI was done using a 3T MRI scanner (Signa GE medical
JAC
system, WN, USA). T1, T2, FLAIR, DW1 and T1 contrast images were
obtained in axial, coronal and sagittal planes. The presence of meningeal
enhancement, granuloma, infarction and hydrocephalus was noted.
Lumbar CSF was analysed for cells, protein and sugar and a CSF smear
was examined for the presence of AFB. CSF BACTEC culture, PCR and IgM
ELISA for Mycobacterium tuberculosis were also conducted.
Randomization and treatment
The patients were randomized to receive either 10 mg/kg/day rifampicin
(maximum of 450 mg/day) or 10 mg/kg/day levofloxacin (maximum of
500 mg/day) using computer-generated random numbers in a 1 :1 ratio.
All the patients received 5 mg/kg/day isoniazid (maximum of 300 mg),
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25 mg/kg/day pyrazinamide (maximum of 1500 mg) and 15 mg/kg/day
ethambutol (maximum of 800 mg).19 The drugs were given orally in the
conscious patients and through nasogastric tube in the unconscious
patients after dissolving in 30 mL of plain water on an empty stomach
and was followed by 20 mL of plain water. Subsequent treatment was
decided by the treating physician. Patients also received 0.5 mg/kg pred-
nisolone (maximum of 40 mg) for 1 month, which was then tapered
over the next 4 weeks. All patients received 150 mg/day aspirin unless
contraindicated. In patients with HIV, antiretroviral treatment was started
after 1 month. Patients having hydrocephalus with raised intracranial
pressure resulting in deterioration of consciousness had a ventriculoperito-
neal shunt fitted. Patients were examined clinically twice daily and liver
function tests were conducted weekly or earlier if indicated during the hos-
pital stay. After discharge, patients were followed up at 1, 3 and 6 months
or earlier if indicated and their outcome and any side effects of the drugs
were recorded. Liver function tests (serum bilirubin, transaminase and
alkaline phosphatase) were measured at 1 and 3 months or earlier if indi-
cated. The cranial MRI was repeated at 6 months in the surviving patients
per protocol and even earlier if clinically indicated.
Serious adverse events (SAEs)
Patients were observed for drug reaction, gastrointestinal symptoms,
jaundice, encephalopathy, seizure, myoclonus and delirium. We used
modified criteria of ATT-induced hepatitis as described by Ungo et al.20
The patients were considered to have ATT-induced hepatitis if there was
a three times increase in transaminase in symptomatic (anorexia,
nausea and vomiting) and five times increase in asymptomatic patients
whose baseline liver function tests were normal. 20 Serum creatinine
.1.6 mg/dL was considered as indicating impaired renal function. In
patients with SAEs, the study drug was stopped and an alternative treat-
ment was prescribed. The presence of isolated gastrointestinal symptoms
was not an indication for stopping the study drug.
Outcome
The primary outcome measure was death at 6 months and the secondary
outcome measures were disability, change in MRI at 6 months and SAEs.
The functional outcome was defined on the basis of the 6 month Barthel
index (BI) score [poor (BI, 12), partial (BI¼12 –19) and complete (BI≥20)
recovery].2
Statistical analysis
The baseline characteristics of the two study groups were compared using
Fisher’s exact test for categorical variables and an independent t-test or
Mann – Whitney U-test for continuous variables. Per-protocol and
intention-to-treat analyses were conducted for death and functional out-
come. Patients with SAEs were also followed up, although they were with-
drawn from the study drug and their 6 month outcome was included in
the group to which they were randomized. Patients lost to follow-up
were included in the poor recovery group. Secondary outcomes were eval-
uated using Fisher’s exact test. Kaplan–Meier survival estimates were used
2247
Kalita et al.

to display the survival of the patients who received levofloxacin or rifam-
picin. The relative risk of death between the levofloxacin and rifampicin
groups was analysed using Cox regression analysis. At least one confound-
ing variable per 10 deaths was adjusted and the variables having the low-
est P value in the univariate analysis were included. Variables were
considered significant if the two-tailed P value was ,0.05. The statistical
analysis was conducted using SPSS version 16.
Results
Recruitment
Primary outcome
At 6 months, 44 patients could be retained in the levofloxacin
group and 56 in the rifampicin group. Levofloxacin had to be dis-
continued more frequently compared with rifampicin due to SAEs
(16 versus 4, P ¼0.01). On per-protocol analysis, there were insig-
nificantly more deaths in the rifampicin arm compared with the
levofloxacin arm (P ¼ 0.14). Eleven out of 44 (25%) patients in
the levofloxacin arm and 23 out of 56 (41.1%) in the rifampicin
arm died. The functional outcome at 6 months was also insignifi-
cantly worse in the rifampicin arm compared with the levofloxacin
arm (5/33 versus 1/33, P ¼ 0.23).

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During the study period, 203 patients with TBM were screened,
120 of whom were randomized (Figure 1).
Patient characteristics
The median age of the patients was 34.5 (16 – 75) years and
53 (44.2%) were females. The baseline clinical, laboratory
and imaging characteristics were similar in both groups
(Tables 1 and 2). During the course of treatment, 17 out of 120
(14.2%) patients needed a ventriculoperitoneal shunt (9 patients
in the levofloxacin group and 8 in the rifampicin group).
In 16 patients, levofloxacin had to be stopped due to SAEs and
2 of them were lost to follow-up. Of the remaining patients, two
died, seven had poor recovery, three partial recovery and two
complete recovery. Rifampicin had to be stopped in four patients
and all of them recovered completely. The patients who were lost
to follow-up were included in the poor recovery group and the
remaining patients were included in their respective group for
intention-to-treat analysis. On intention-to-treat analysis, death
in the levofloxacin arm was insignificantly lower compared with
the rifampicin arm [13 (21.7%) versus 23 (38.3%), P ¼ 0.07]. The
details of per-protocol and intention-to-treat analyses are

Enrolment Assessed for eligibility (n = 203)

Excluded (n = 83)
Seizure (n = 45)
Seizure + prior ATT (n = 19)
Prior ATT (n = 11)
Paediatric age (n = 8)

Randomized (n = 120)

Levofloxacin (n = 60) Allocation Rifampicin (n = 60)

Withdrawn due to SAE (n = 16) Follow-up Withdrawn due to SAE (n = 4)

6 month follow-up (n = 44) Analysis 6 month follow-up (n = 56)

Death (n = 11) Death (n = 23)
Survival (n = 33) Survival (n = 33)

Figure 1. Study flow chart.

2248
Levofloxacin versus rifampicin in tuberculous meningitis JAC
Table 1. Comparison of baseline clinical characteristics in patients with Figure 2). Mortality was related to the stage of meningitis
TBM receiving levofloxacin or rifampicin (P ¼ 0.0001); 1 (2.8%) patient with stage I, 17 (47.2%) with
stage II and 18 (50.0%) with stage III meningitis died. CSF bac-
Levofloxacin Rifampicin teriological confirmatory tests were conducted in 116 patients;
Parameter (n¼60) (n¼60) P value of them, 34 died. In definite TBM, 12 (35.3%) patients died and
in the highly probable group 21 (61.8%) died (P ¼ 0.88). Of the def-
Age (years), mean+SD 39.3+16.5 38.0+18.5 0.42 inite cases who died, three patients received levofloxacin and nine
Female 29 24 0.36 rifampicin (P ¼ 0.17). The cause of death was disease per se in 22
Duration of illness (weeks) 10.51+9.36 11.11+9.23 0.72 (infarction and hydrocephalus), secondary infection in 9, aspir-
Diabetes 7 7 1.00 ation in 3 and shunt complications in 2 patients.
Hypertension 4 9 0.14
Ischaemic heart disease 3 0 0.08

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Secondary outcome
GCS score 11.8+3.1 12.4+3.2 0.31
Focal weakness 24 22 0.85 The functional outcome at 6 months in the levofloxacin group
Extra-CNS tuberculosis 14 16 0.67 was poor in 10 (21.3%), partial in 10 (21.3%) and complete in
HIV positive 1 3 0.31 27 (57.4%) patients. In the rifampicin group, these values were
5 (13.5%), 6 (16.2%) and 26 (70.3%) patients, respectively
Stage of TBM (P ¼ 0.47). At 6 months, a total of 36 patients died and in 20
I 9 12 0.70 patients follow-up MRI was not conducted as their study drug
II 33 33 was withdrawn due to SAEs. Therefore, follow-up MRI studies
III 18 15 are available in 66 patients (33 in each group) only. The repeat
MRI findings at 6 months did not reveal significant difference
between the levofloxacin arm and the rifampicin arm with respect
Table 2. Laboratory and MRI findings in the patients with TBM receiving to the appearance of new infarction (2 versus 3, P ¼0.64), appear-
levofloxacin or rifampicin ance or enlargement of tuberculoma (18 versus 18, P ¼ 1.00),
hydrocephalus (9 versus 7, P ¼ 0.57) or exudates (9 versus 5,
Levofloxacin Rifampicin P ¼ 0.23). The patients in the levofloxacin arm had a significantly
Parameter (n ¼60) (n ¼60) P value higher frequency of seizures compared with the patients in the
rifampicin arm (15/60 versus 4/60, P¼ 0.006). In the levofloxacin
CSF arm, three patients developed myoclonus and one patient devel-
cells/mm3 183+217 313+822 0.96 oped encephalopathy. Transaminase levels were insignificantly
protein (mg/dL) 192.4+166.5 196.7+167.9 0.75 higher in the rifampicin group compared with the levofloxacin
glucose (mg/dL) 42.1+31.9 47.4+33.1 0.40 group (178+270 versus 139+144 U/L, P ¼ 0.76) (Table 4).
bacteriologically confirmeda 18 24 0.17 Levofloxacin-induced complications occurred in the first week in
serum bilirubin (mg/dL) 1.2+1.5 0.92+0.98 0.23 8, the second week in 10 and after the second week in 9 patients.
SGPT (U/L) 75+96 86+146 0.75 In the rifampicin group, complications were noted in the first week
serum albumin (g/dL) 3.4+0.7 3.4+0.8 0.75 in 11, the second week in 7, the third to fourth week in 4 and after
serum creatinine (mg/dL) 1.0+0.5 0.9+0.4 0.28 the fourth week in 5 patients.
serum sodium (mEq/L) 132+8.0 134.0+8.0 0.15

MRI findings Discussion

abnormal 54 51 0.58 In the present study, the survival of TBM patients at 6 months was
exudate 25 22 0.62 significantly better in the levofloxacin arm compared with the
hydrocephalus 25 26 0.86 rifampicin arm, although the functional outcome was not signifi-
tuberculoma 27 25 0.77 cantly different. The role of fluoroquinolones in the treatment of
infarction 26 26 1.00 tuberculosis has been evaluated mostly in pulmonary tubercu-
losis.21,22 The efficacy of quinolones in TBM has been evaluated
SGPT, serum alanine transferase. in two studies only. In one study in 61 patients with TBM, the
a
Positive AFB in smear/culture, IgM ELISA and PCR. role of ciprofloxacin, gatifloxacin and levofloxacin in addition to
standard ATT was compared. The CSF penetration was maximal
for levofloxacin followed by gatifloxacin and ciprofloxacin. There
presented in Table 3. Twenty-seven patients died within 1 month was a U-shaped response; the worst outcome was in the patients
of treatment, 6 within 1 – 3 months and 3 within 3 – 6 months. with the lowest and the highest plasma and CSF quinolone expos-
Kaplan – Meier analysis of survival revealed significantly higher ure compared with those with intermediate quinolone expos-
survival in the levofloxacin group compared with the rifampicin ure.23 We therefore chose 500 mg/day levofloxacin to optimize
group [47 (78.3%) versus 37 (61.7%)]. On Cox regression analysis, the benefit based on its U-shaped response. Moreover, levofloxa-
survival was significantly better in the levofloxacin group com- cin had to be withdrawn in 16 of our patients even at the dose of
pared with the rifampicin group after adjusting for covariates of 500 mg/day due to seizure, myoclonus or encephalopathy. The
survival such as age, GCS score, stage of TBM, focal weakness higher incidence of seizures following levofloxacin in our study
and infarction (hazard ratio 2.13, 95% CI 1.04 – 4.34, P ¼ 0.04; may be due to more severe meningitis or a genetic susceptibility.

2249
Kalita et al.

Table 3. Outcome of the patients with TBM in the levofloxacin and rifampicin groups using per-protocol and intention-to-treat analyses

Parameter Levofloxacin (n¼60) Rifampicin (n¼60) P value of PPA/ITTA

Primary outcome PPA (n¼44)/ITTA (n¼60) PPA (n¼56)/ITTA (n¼60)

death 11 (25%)/13 (21.7%) 23 (41.1%)/23 (38.3%) 0.14/0.07

Functional outcome PPA (n¼33)/ITTA (n¼47) PPA (n¼33)/ITTA (n¼37)

poor 1 (3.0%)/10 (21.3%) 5 (15.1%)/5 (13.5%) 0.23/0.47
partial 7 (21.2%)/10 (21.3%) 6 (18.2%)/6 (16.2%)
complete 25 (75.8%)/27 (57.4%) 22 (66.7%)/26 (70.3%)

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ITTA, intention-to-treat analysis; PPA, per-protocol analysis.

Table 4. Adverse events recorded in the patients with TBM receiving

1.0
levofloxacin or rifampicin

Levofloxacin Levofloxacin Rifampicin

Rifampicin
0.9 Side effect (n¼60) (n¼60) P value
Cumulative survival

Seizure 15 4 0.006
Myoclonus 3 0 0.08
Encephalopathy 1 0 0.32
0.8
Serum bilirubin (mg/dL)a 1.8+2.2 1.6+1.8 0.73
SGPT (U/L)a 139+144 178+270 0.76
Withdrawal of drugs 16 4 0.01
0.7
SGPT, serum alanine transferase.
a
Highest values during the study period.

0.6 Adjusted hazard ratio 2.13 (95% CI 1.04-4.34); P = 0.04

The limitations of the present study are that it is a single-centre
0 30 60 90 120 150 180 study from a tertiary referral teaching institute and has an open-
Number at risk Time (days) label design. A large number of patients could not be randomized
Levofloxacin 60 48 47 47 47 47 47 due to seizure at presentation or already being on ATT. Moreover, in
Rifampicin 60 42 40 38 37 37 37 many patients, levofloxacin had to be withdrawn due to SAEs. It
Figure 2. Survival analysis using Cox regression shows cumulative survival would have been better to exclude the patients with structural
of the TBM patients receiving levofloxacin and rifampicin after adjustment brain lesions, particularly in the frontotemporal region, because of
for covariates. potential for seizures especially if exposed to seizurogenic drugs.
The present study is also underpowered. A multicentre study
The seizurogenic potential of quinolones has also been reported in using levofloxacin as an add-on antitubercular drug is in progress.30
earlier studies.24,25 From this study, it can be concluded that levofloxacin in TBM
MRI changes at 6 months were not significantly different results in better survival at 6 months compared with rifampicin,
between the levofloxacin and rifampicin arms. Only five patients although disability was not different between the two groups.
developed infarction at follow-up, which is much lower than in our Levofloxacin may be used as an alternative drug to rifampicin
earlier reports in which 32% – 40% of patients developed infarc- especially in patients with hepatic dysfunction who do not have
tion after initiation of ATT.15,26,27 The lower frequency of infarction seizure.
in the present study may be due to the use of both corticosteroid
and aspirin. We used a relatively lower dose of corticosteroid com- Acknowledgements
pared with the study from Vietnam in which 0.3 –0.4 mg/kg dexa-
We thank Mr Rakesh Kumar Nigam for secretarial help.
methasone was used and tapered over 6 – 8 weeks. Long-term
follow-up revealed insignificantly higher survival at 2 years but
not at 5 years.28 In our earlier studies, we have used 10 mg/kg Funding
methyl prednisolone intravenously for 5 days in TBM and it did This study was carried out as a part of routine patient care.
not result in improvement in clinical and in somatosensory and
motor evoked potentials compared with those who were not on
methylprednisolone. 17,29 In the present study, therefore, we Transparency declarations
used a low dose of corticosteroid. None to declare.

2250
Levofloxacin versus rifampicin in tuberculous meningitis
Author contributions
J. K. was involved in protocol design, randomization, data analysis and
writing the manuscript, U. K. M. was involved in planning the study and
writing the manuscript, S. P. was involved in the clinical evaluation,
follow-up and data collection and S. K. B. was involved in analysis of data.
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