Journal of Antimicrobial Chemotherapy Advance Access published April 20, 2014

J Antimicrob Chemother
doi:10.1093/jac/dku103

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

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).
Downloaded from http://jac.oxfordjournals.org/ by guest on May 24, 2015

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 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 0.04). The functional outcome (P 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 rifampicin arm had poor recovery. Repeat MRI findings did not differ between the groups. Levofloxacin was discontinued more frequently than rifampicin due to SAEs (16 versus 4, P 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 rifampicin 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. Druginduced hepatitis is more common in Asians and has been
reported in 26% 36% of patients.12,13 Of the first-line antitubercular drugs, isoniazid, pyrazinamide and rifampicin have hepatotoxic 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 antitubercular drugs. Of the candidate drugs, clarithromycin and fluoroquinolones 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 penetration compared with other quinolones and have been evaluated

# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com

1 of 6

Kalita et al.

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

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 criteria included the following: (i) CSF cells 0.2109/L with lymphocytic predominance, protein .1 g/L, sterile bacterial and fungal culture and
absence of cryptococcal antigen; (ii) MRI evidence of exudates, hydrocephalus, 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 illness, presence of focal neurological deficit, seizure, evidence of raised
intracranial pressure (hyperventilation and extensor posturing) and evidence 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

2 of 6

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),
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 prednisolone (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 ventriculoperitoneal shunt fitted. Patients were examined clinically twice daily and liver
function tests were conducted weekly or earlier if indicated during the hospital 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 indicated. 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 treatment 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 (BI12 19) and complete (BI20)
recovery].2

Statistical analysis
The baseline characteristics of the two study groups were compared using
Fishers 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 outcome. Patients with SAEs were also followed up, although they were withdrawn 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 evaluated using Fishers exact test. KaplanMeier survival estimates were used

Downloaded from http://jac.oxfordjournals.org/ by guest on May 24, 2015

This is an investigator-initiated, single-centre, open-label randomized controlled trial comparing the efficacy and safety of levofloxacin versus rifampicin 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 0.05 and type II error b0.15
using Fishers 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 sample size was 64 in each arm.

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.

JAC

Levofloxacin versus rifampicin in tuberculous meningitis

to display the survival of the patients who received levofloxacin or rifampicin. The relative risk of death between the levofloxacin and rifampicin
groups was analysed using Cox regression analysis. At least one confounding variable per 10 deaths was adjusted and the variables having the lowest 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
During the study period, 203 patients with TBM were screened,
120 of whom were randomized (Figure 1).

Patient characteristics

Enrolment

At 6 months, 44 patients could be retained in the levofloxacin

group and 56 in the rifampicin group. Levofloxacin had to be discontinued more frequently compared with rifampicin due to SAEs
(16 versus 4, P 0.01). On per-protocol analysis, there were insignificantly more deaths in the rifampicin arm compared with the
levofloxacin arm (P 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 insignificantly worse in the rifampicin arm compared with the levofloxacin
arm (5/33 versus 1/33, P 0.23).
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 0.07]. The
details of per-protocol and intention-to-treat analyses are

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)

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

Analysis

6 month follow-up (n = 56)

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

Figure 1. Study flow chart.

3 of 6

Downloaded from http://jac.oxfordjournals.org/ by guest on May 24, 2015

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).

Primary outcome

Kalita et al.

Table 1. Comparison of baseline clinical characteristics in patients with

TBM receiving levofloxacin or rifampicin
Levofloxacin
(n60)

Rifampicin
(n60)

P value

Age (years), mean+SD

Female
Duration of illness (weeks)
Diabetes
Hypertension
Ischaemic heart disease
GCS score
Focal weakness
Extra-CNS tuberculosis
HIV positive

39.3+16.5
29
10.51+9.36
7
4
3
11.8+3.1
24
14
1

38.0+18.5
24
11.11+9.23
7
9
0
12.4+3.2
22
16
3

0.42
0.36
0.72
1.00
0.14
0.08
0.31
0.85
0.67
0.31

Stage of TBM
I
II
III

9
33
18

12
33
15

0.70

Table 2. Laboratory and MRI findings in the patients with TBM receiving
levofloxacin or rifampicin
Levofloxacin
(n 60)

Rifampicin
(n 60)

P value

CSF
cells/mm3
protein (mg/dL)
glucose (mg/dL)
bacteriologically confirmeda
serum bilirubin (mg/dL)
SGPT (U/L)
serum albumin (g/dL)
serum creatinine (mg/dL)
serum sodium (mEq/L)

183+217
192.4+166.5
42.1+31.9
18
1.2+1.5
75+96
3.4+0.7
1.0+0.5
132+8.0

313+822
196.7+167.9
47.4+33.1
24
0.92+0.98
86+146
3.4+0.8
0.9+0.4
134.0+8.0

0.96
0.75
0.40
0.17
0.23
0.75
0.75
0.28
0.15

MRI findings
abnormal
exudate
hydrocephalus
tuberculoma
infarction

54
25
25
27
26

51
22
26
25
26

0.58
0.62
0.86
0.77
1.00

Parameter

The functional outcome at 6 months in the levofloxacin group

was poor in 10 (21.3%), partial in 10 (21.3%) and complete in
27 (57.4%) patients. In the rifampicin group, these values were
5 (13.5%), 6 (16.2%) and 26 (70.3%) patients, respectively
(P 0.47). At 6 months, a total of 36 patients died and in 20
patients follow-up MRI was not conducted as their study drug
was withdrawn due to SAEs. Therefore, follow-up MRI studies
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
to the appearance of new infarction (2 versus 3, P 0.64), appearance or enlargement of tuberculoma (18 versus 18, P 1.00),
hydrocephalus (9 versus 7, P 0.57) or exudates (9 versus 5,
P 0.23). The patients in the levofloxacin arm had a significantly
higher frequency of seizures compared with the patients in the
rifampicin arm (15/60 versus 4/60, P 0.006). In the levofloxacin
arm, three patients developed myoclonus and one patient developed encephalopathy. Transaminase levels were insignificantly
higher in the rifampicin group compared with the levofloxacin
group (178+270 versus 139+144 U/L, P 0.76) (Table 4).
Levofloxacin-induced complications occurred in the first week in
8, the second week in 10 and after the second week in 9 patients.
In the rifampicin group, complications were noted in the first week
in 11, the second week in 7, the third to fourth week in 4 and after
the fourth week in 5 patients.

Discussion

SGPT, serum alanine transferase.

a
Positive AFB in smear/culture, IgM ELISA and PCR.

presented in Table 3. Twenty-seven patients died within 1 month

of treatment, 6 within 1 3 months and 3 within 3 6 months.
Kaplan Meier analysis of survival revealed significantly higher
survival in the levofloxacin group compared with the rifampicin
group [47 (78.3%) versus 37 (61.7%)]. On Cox regression analysis,
survival was significantly better in the levofloxacin group compared with the rifampicin group after adjusting for covariates of
survival such as age, GCS score, stage of TBM, focal weakness
and infarction (hazard ratio 2.13, 95% CI 1.04 4.34, P 0.04;

4 of 6

Secondary outcome

In the present study, the survival of TBM patients at 6 months was

significantly better in the levofloxacin arm compared with the
rifampicin arm, although the functional outcome was not significantly different. The role of fluoroquinolones in the treatment of
tuberculosis has been evaluated mostly in pulmonary tuberculosis.21,22 The efficacy of quinolones in TBM has been evaluated
in two studies only. In one study in 61 patients with TBM, the
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
was a U-shaped response; the worst outcome was in the patients
with the lowest and the highest plasma and CSF quinolone exposure compared with those with intermediate quinolone exposure.23 We therefore chose 500 mg/day levofloxacin to optimize
the benefit based on its U-shaped response. Moreover, levofloxacin had to be withdrawn in 16 of our patients even at the dose of
500 mg/day due to seizure, myoclonus or encephalopathy. The
higher incidence of seizures following levofloxacin in our study
may be due to more severe meningitis or a genetic susceptibility.

Downloaded from http://jac.oxfordjournals.org/ by guest on May 24, 2015

Parameter

Figure 2). Mortality was related to the stage of meningitis

(P 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 bacteriological confirmatory tests were conducted in 116 patients;
of them, 34 died. In definite TBM, 12 (35.3%) patients died and
in the highly probable group 21 (61.8%) died (P 0.88). Of the definite cases who died, three patients received levofloxacin and nine
rifampicin (P 0.17). The cause of death was disease per se in 22
(infarction and hydrocephalus), secondary infection in 9, aspiration in 3 and shunt complications in 2 patients.

JAC

Levofloxacin versus rifampicin in tuberculous meningitis

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

Levofloxacin (n60)

Rifampicin (n60)

P value of PPA/ITTA

Primary outcome
death

PPA (n44)/ITTA (n60)

11 (25%)/13 (21.7%)

PPA (n56)/ITTA (n60)

23 (41.1%)/23 (38.3%)

0.14/0.07

Functional outcome
poor
partial
complete

PPA (n33)/ITTA (n47)

1 (3.0%)/10 (21.3%)
7 (21.2%)/10 (21.3%)
25 (75.8%)/27 (57.4%)

PPA (n33)/ITTA (n37)

5 (15.1%)/5 (13.5%)
6 (18.2%)/6 (16.2%)
22 (66.7%)/26 (70.3%)

0.23/0.47

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

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

levofloxacin or rifampicin

1.0

Cumulative survival

0.9

Side effect

0.8

Seizure
Myoclonus
Encephalopathy
Serum bilirubin (mg/dL)a
SGPT (U/L)a
Withdrawal of drugs

Levofloxacin
(n60)

Rifampicin
(n60)

P value

15
3
1
1.8+2.2
139+144
16

4
0
0
1.6+1.8
178+270
4

0.006
0.08
0.32
0.73
0.76
0.01

0.7
SGPT, serum alanine transferase.
Highest values during the study period.

0.6

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

0

Number at risk
Levofloxacin 60
Rifampicin
60

30
48
42

120
90
Time (days)
47
47
47
40
38
37

60

150

180

47
37

47
37

Figure 2. Survival analysis using Cox regression shows cumulative survival

of the TBM patients receiving levofloxacin and rifampicin after adjustment
for covariates.

The seizurogenic potential of quinolones has also been reported in

earlier studies.24,25
MRI changes at 6 months were not significantly different
between the levofloxacin and rifampicin arms. Only five patients
developed infarction at follow-up, which is much lower than in our
earlier reports in which 32% 40% of patients developed infarction after initiation of ATT.15,26,27 The lower frequency of infarction
in the present study may be due to the use of both corticosteroid
and aspirin. We used a relatively lower dose of corticosteroid compared with the study from Vietnam in which 0.3 0.4 mg/kg dexamethasone 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
methyl prednisolone intravenously for 5 days in TBM and it did
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
used a low dose of corticosteroid.

The limitations of the present study are that it is a single-centre

study from a tertiary referral teaching institute and has an openlabel design. A large number of patients could not be randomized
due to seizure at presentation or already being on ATT. Moreover, in
many patients, levofloxacin had to be withdrawn due to SAEs. It
would have been better to exclude the patients with structural
brain lesions, particularly in the frontotemporal region, because of
potential for seizures especially if exposed to seizurogenic drugs.
The present study is also underpowered. A multicentre study
using levofloxacin as an add-on antitubercular drug is in progress.30
From this study, it can be concluded that levofloxacin in TBM
results in better survival at 6 months compared with rifampicin,
although disability was not different between the two groups.
Levofloxacin may be used as an alternative drug to rifampicin
especially in patients with hepatic dysfunction who do not have
seizure.

Acknowledgements
We thank Mr Rakesh Kumar Nigam for secretarial help.

Funding
This study was carried out as a part of routine patient care.

Transparency declarations
None to declare.

5 of 6

Downloaded from http://jac.oxfordjournals.org/ by guest on May 24, 2015

Levofloxacin
Rifampicin

Kalita et al.

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.

References
1 Dye C, Scheele S, Dolin P et al. Consensus statement. Global burden of
tuberculosis: estimated incidence, prevalence and mortality by country.
World Health Organization surveillance and monitoring project. JAMA
1999; 282: 67786.
2 Kalita J, Misra UK, Ranjan P. Predictors of long-term neurological
sequelae of tuberculous meningitis: a multivariate analysis. Eur J Neurol
2007; 14: 33 7.
3 Thwaites GE. The diagnosis and management of tuberculous
meningitis. Practical Neurology 2002; 2: 25061.

5 Peloquin CA. Antituberculosis drugs: pharmacokinetics. In: Heifets LB,

ed. Drug Susceptibility in the Chemotherapy of Mycobacterial Infections.
Boca Raton: CRC Press, 1991; 13 57.
6 Mindermann T, Zimmerli W, Gratzl O. Rifampin concentrations in various
compartments of the human brain: a novel method for determining drug
levels in the cerebral extracellular space. Antimicrob Agents Chemother
1998; 42: 2626 9.
7 Cheng IK, Chan PC, Chan MK. Tuberculous peritonitis complicating
long-term peritoneal dialysis. Report of 5 cases and review of the
literature. Am J Nephrol 1989; 9: 155 61.
8 Girgis NI, Yassin MW, Laughlin LW et al. Rifampicin in the treatment of
tuberculous meningitis. J Trop Med Hyg 1978; 81: 2467.
9 Chandra B. Some aspects of tuberculous meningitis in Surabaya. Proc
Aust Assoc Neurol 1976; 13: 73 81.
10 Thwaites GE, Lan NT, 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: 7988.
11 Ruslami R, Ganiem AR, Dian S et al. Intensified regimen containing
rifampicin and moxifloxacin for tuberculous meningitis: an open-label,
randomised controlled phase 2 trial. Lancet Infect Dis 2013; 13: 2735.
12 Parthasarathy R, Sarma GR, Janardhanam B et al. Hepatic toxicity in South
Indian patients during treatment of tuberculosis with short-course regimens
containing isoniazid, rifampicin and pyrazinamide. Tubercle 1986; 67: 99108.
13 Mehta S. Malnutrition and drugs: clinical implications. Dev Pharmacol
Ther 1990; 15: 15965.
14 Yew WW, Chan CK, Leung CC et al. Comparative roles of levofloxacin
and ofloxacin in the treatment of multidrug-resistant tuberculosis:

6 of 6

15 Misra UK, Kalita J, Nair PP. Role of aspirin in tuberculous meningitis: a

randomized open label placebo controlled trial. J Neurol Sci 2010;
293: 12 7.
16 Patel VB, Padayatchi N, Bhigjee AI et al. Multidrug-resistant
tuberculous meningitis in KwaZulu-Natal, South Africa. Clin Infect Dis
2004; 38: 8516.
17 Misra UK, Kalita J, Roy AK et al. Role of clinical, radiological, and
neurophysiological changes in predicting the outcome of tuberculous
meningitis: a multivariable analysis. J Neurol Neurosurg Psychiatry 2000;
68: 300 3.
18 British Medical Research Council. Streptomycin in tuberculosis trials
committee: streptomycin treatment of tuberculous meningitis. Lancet
1948; 1: 58296.
19 WHO. Global Tuberculosis Control: Surveillance, Planning, Financing.
WHO Report 2005, WHO/HTM/TB/2005.349. Geneva: WHO, 2005.
20 Ungo JR, Jones D, Ashkin D et al. Antituberculosis drug-induced
hepatotoxicity. Am J Respir Crit Care Med 1998; 157: 1871 6.
21 Tahaoglu K, Torun T, Sevim Tet al. The treatment of multidrug-resistant
tuberculosis in Turkey. N Engl J Med 2001; 345: 1704.
22 Richeldi L, Covi M, Ferrara G et al. Clinical use of levofloxacin in the
long-term treatment of drug resistant tuberculosis. Monaldi Arch Chest
Dis 2002; 57: 3943.
23 Thwaites GE, Bhavnani SM, Chau TT et al. Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones
for tuberculous meningitis. Antimicrob Agents Chemother 2011; 55:
3244 53.
24 Bellon A, Perez-Garcia G, Coverdale JH et al. Seizures associated with
levofloxacin: case presentation and literature review. Eur J Clin
Pharmacol 2009; 65: 959 62.
25 Misra UK, Kalita J, Chandra S et al. Association of antibiotics with status
epilepticus. Neurol Sci 2013; 34: 327 31.
26 Kalita J, Prasad S, Maurya PK et al. MR angiography in tuberculous
meningitis. Acta Radiol 2012; 53: 324 9.
27 Kalita J, Misra UK, Nair PP. Predictors of stroke and its significance in the
outcome of tuberculous meningitis. J Stroke Cerebrovasc Dis 2009;
18: 251 8.
28 Torok ME, Nguyen DB, Tran TH et al. Dexamethasone and long-term
outcome of tuberculous meningitis in Vietnamese adults and
adolescents. PLoS One 2011; 6: e27821.
29 Kalita J, Misra UK. Effect of methyl prednisolone on sensory motor
functions in tuberculous meningitis. Neurol India 2001; 49: 267 71.
30 Heemskerk D, Day J, Chau TTet al. Intensified treatment with high dose
rifampicin and levofloxacin compared to standard treatment for adult
patients with tuberculous meningitis (TBM-IT): protocol for a randomized
controlled trial. Trials 2011; 2: 12 25.

Downloaded from http://jac.oxfordjournals.org/ by guest on May 24, 2015

4 Ellard GA, Humphries MJ, Allen BW. Cerebrospinal fluid drug

concentrations and the treatment of tuberculous meningitis. Am Rev
Respir Dis 1993; 148: 6505.

preliminary results of a retrospective study from Hong Kong. Chest 2003;

124: 1476 81.