J. Antimicrob. Chemother. 2014 Kalita Jac Dku103

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Safety and efficacy of levofloxacin versus rifampicin in tuberculousmeningitis: 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: [email protected] or [email protected]

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 diagnosedon the basis of clinical, MRI and CSF findings were included. Patients with hepatic or renal dysfunction, organtransplantation, 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) orrifampicin (10 mg/kg, maximum 450 mg). They also received isoniazid, pyrazinamide, ethambutol, prednisoloneand aspirin. The primary outcome was death and secondary outcome measures were 6 month disability, repeatMRI 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 weresimilar between the two groups. At 6 months, 13 out of 60 (21.7%) patients in the levofloxacin arm and 23out of 60 (38.3%) patients in the rifampicin arm had died ( P ¼0.07). On Cox regression analysis, survival in thelevofloxacin group was significantly better than in the rifampicin group (hazard ratio 2.13, 95% CI 1.04–4.34,P ¼0.04). The functional outcome (P ¼0.47) 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, P ¼0.01).

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 withtuberculosis.1 It results in death or severe disability in nearlyhalf of affected patients.2 The introduction of rifampicin andpyrazinamide has not resulted in further decline of mortalityover isoniazid and streptom ycin.3,4 Rifampicin is bactericidal buthas poor CSF penetration.5 The concentration of rifampicin hasbeen found tobe below theMICin two studies.6,7Theuse of rifam-picin in TBM is based on a few trials that are not class I.8,9The roleof rifampicin in the treatment of TBM was highlighted in a study inwhich all patients resistant to isoniazid and rifampicin died, butonly 28.7% died who were susceptible to antitubercular drugs.10

In a recent study, 450 mg of rifampicin orally resulted in a CSFconcentration below the assay level (0.26 mg/L) in 64% of patients, whereas 600 mg of rifampicin intravenously resulted ina higher CSF concentration and only 4% were below the assay

level. The higher dose of rifampicin in that study was associatedwith lower 6 month mortality without significant increase inhepatotoxicity.11

Besides the CSF penetration and efficacy of antituberculardrugs, the safety profile of the drug is also important. Drug-induced hepatitis is more common in Asians and has beenreported 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, hepatotoxicityand a paucity of strong evidence for the benefit of a standarddose 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 morepromising. Quinolones are bactericidal, have no hepatotoxicityand have been reported to be beneficial in multidrug-resistanttuberculosis.14 Moxifloxacin and levofloxacin have higher CSF pene-tration 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: [email protected]

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Journal of Antimicrobial Chemotherapy Advance Access published April 20, 2014



in a few studies as an add-on or alternative to ethambutol.10,11 Inthe 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 theefficacy and safety of levofloxacin versus rifam-picin in patients with TBM in addition to isoniazid, pyrazinamide andethambutol. The study was conducted in a tertiary care teaching hospitalin India. The protocol was designed by the first and second authors.Consecutive TBM patients admitted to the neurologyservice were enrolledfrom July 2009 to June 2012. The study was approved by the Local EthicsCommittee (no. A-15:PGI/DM/IEC/50/13.4.2010) and was retrospectivelyregistered in the Clinical Trial Registry, India (CTRI/2012/11/003155). Thepatients or their representatives gave informed consent. The sample sizewas calculated keeping the type I error a¼0.05 and type II error b¼0.15using Fisher’sexact test. Weconsidered the absolute reductionin deaths inthe 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 CSFfindings. Essential criteria included the presence of meningitis symptomsconsisting of fever, headache or vomiting for ≥2 weeks in patients inwhom malaria, septic and fungal meningitis wereexcluded. Supportive cri-teria included thefollowing: (i) CSFcells≥0.2×109/L with lymphocytic pre-dominance, protein .1 g/L, sterile bacterial and fungal culture andabsence of cryptococcalantigen;(ii) MRIevidenceof exudates, hydroceph-alus, infarction or tuberculoma; and (iii) extra-CNS tuberculosis.

Thepresenceof essential criteria and anytwo of thesupportive criteriawas considered as TBM. The presence of acid-fast bacilli (AFB) in the CSFsmear 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-standingimmunosuppressive therapy, organ transplantation, pregnancy, lactation,age ,15 years and prior antitubercular treatment (ATT) for ≥1 monthwere excluded.

Evaluation

Patients were subjected to detailed clinical evaluation. The duration of ill-ness, presence of focal neurological deficit, seizure, evidence of raisedintracranial pressure (hyperventilation and extensor posturing) and evi-dence of extra-CNS tuberculosis (lymph node, lungs, abdomen and boneand joint) were noted. Consciousness was assessed by the Glasgow Coma

Scale (GCS).The presenceof cranial nervepalsy wasnoted. Focalweaknesswas 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 stageIII, meningitis with GCS score ,11.18

Investigations

Blood counts, erythrocyte sedimentation rate, haemoglobin, blood sugar,serum creatinine, albumin, bilirubin, transaminase and electrolytes weremeasured at admission and were repeated when required. Radiographof the chest, electrocardiogram and HIV serology were performed in allpatients. Cranial MRI was done using a 3T MRI scanner (Signa GE medical

system, WN, USA). T1, T2, FLAIR, DW1 and T1 contrast images wereobtained in axial, coronal and sagittal planes. The presence of meningealenhancement, granuloma, infarction and hydrocephalus was noted.Lumbar CSF was analysed for cells, protein and sugar and a CSF smearwas examined for the presence of AFB. CSF BACTEC culture, PCR and IgMELISA 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),25 mg/kg/day pyrazinamide (maximum of 1500 mg) and 15 mg/kg/dayethambutol (maximum of 800 mg).19 The drugs were given orally in theconscious patients and through nasogastric tube in the unconsciouspatients after dissolving in 30 mL of plain water on an empty stomachand was followed by 20 mL of plain water. Subsequent treatment wasdecided by the treating physician. Patients also received 0.5 mg/kg pred-nisolone (maximum of 40 mg) for 1 month, which was then taperedover the next 4 weeks. All patients received 150 mg/day aspirin unlesscontraindicated. In patients with HIV, antiretroviral treatment was startedafter 1 month. Patients having hydrocephalus with raised intracranialpressureresulting in deterioration of consciousness had a ventriculoperito-neal shunt fitted. Patients were examined clinically twice daily and liverfunction testswereconductedweeklyor earlier if indicatedduring thehos-pital stay. After discharge, patients were followed up at 1, 3 and 6 monthsor earlier if indicated and their outcome and any side effects of the drugswere recorded. Liver function tests (serum bilirubin, transaminase andalkaline phosphatase) were measured at 1 and 3 months or earlier if indi-cated. The cranial MRI was repeated at 6 months in the surviving patientsper protocol and even earlier if clinically indicated.

Serious adverse events (SAEs)

Patients were observed for drug reaction, gastrointestinal symptoms, jaundice, encep halop athy, seizure , myoclonus and delir ium. 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 wasa three times increase in transaminase in symptomatic (anorexia,nausea and vomiting) and five times increase in asymptomatic patientswhose baseline liver function tests were normal.20 Serum creatinine.1.6 mg/dL was considered as indicating impaired renal function. Inpatients with SAEs, the study drug was stopped and an alternative treat-ment was prescribed. The presence of isolated gastrointestinal symptomswas not an indication for stopping the study drug.

Outcome

The primary outcomemeasurewas death at 6 months and thesecondaryoutcome measures were disability, change in MRI at 6 months and SAEs.The functional outcome was defined on the basis of the 6 month Barthelindex(BI) score[ poor (BI,12), partial (BI¼12–19) andcomplete (BI≥20)

recovery].2

Statistical analysis

The baseline characteristics of thetwo studygroups were compared usingFisher’s exact test for categorical variables and an independent t-test orMann–Whitney U-test for continuous variables. Per-protocol andintention-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 inthe group to which they were randomized. Patients lost to follow-upwere included in the poor recoverygroup. Secondary outcomes were eval-uated using Fisher’sexact test. Kaplan–Meier survival estimates wereused

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to display the survival of the patients who received levofloxacin or rifam-picin. The relative risk of death between the levofloxacin and rifampicingroups was analysed usingCox 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 wereconsidered 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

The median age of the patients was 34.5 (16–75) years and53 (44.2%) were females. The baseline clinical, laboratoryand 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 patientsin the levofloxacin group and 8 in the rifampicin group).

Primary outcome

At 6 months, 44 patients could be retained in the levofloxacingroup 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 thelevofloxacin arm (P ¼0.14). Eleven out of 44 (25%) patients inthe levofloxacin arm and 23 out of 56 (41.1%) in the rifampicinarm died. The functional outcome at 6 months was also insignifi-cantly worse in the rifampicin armcompared with thelevofloxacinarm (5/33 versus 1/33, P ¼0.23).

In 16 patients, levofloxacin had to be stopped due to SAEs and2 of them were lost to follow-up. Of the remaining patients, twodied, seven had poor recovery, three partial recovery and twocomplete recovery. Rifampicin had to be stopped in four patientsand all of them recovered completely. The patients who were lostto follow-up were included in the poor recovery group and theremaining patients were included in their respective group forintention-to-treat analysis. On intention-to-treat analysis, death

in the levofloxacin arm was insignificantly lower compared withthe rifampicin arm [13 (21.7%) versus 23 (38.3%), P ¼0.07]. Thedetails 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)

6 month follow-up (n = 44)

Death (n = 11)

Survival (n = 33)

Withdrawn due to SAE (n = 16)

Levofloxacin (n = 60)

Withdrawn due to SAE (n = 4)

Rifampicin (n = 60)

6 month follow-up (n = 56)

Death (n = 23)

Survival (n = 33)

Allocation

Analysis

Follow-up

Randomized (n = 120)

Enrolment

Figure 1. Study flow chart.

Levofloxacin versus rifampicin in tuberculous meningitis

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presented in Table 3. Twenty-seven patients died within 1 monthof treatment, 6 within 1–3 months and 3 within 3–6 months.Kaplan–Meier analysis of survival revealed significantly highersurvival in the levofloxacin group compared with the rifampicingroup [47 (78.3%) versus 37 (61.7%)]. On Cox regression analysis,survival was significantly better in the levofloxacin group com-pared with the rifampicin group after adjusting for covariates of survival such as age, GCS score, stage of TBM, focal weaknessand infarction (hazard ratio 2.13, 95% CI 1.04–4.34, P ¼0.04;

Figure 2). Mortality was related to the stage of meningitis(P ¼0.0001); 1 (2.8%) patient with stage I, 17 (47.2%) withstage II and 18 (50.0%) with stage III meningitis died. CSF bac-teriological confirmatory tests were conducted in 116 patients;of them, 34 died. In definite TBM, 12 (35.3%) patients died andin the highly probable group 21 (61.8%) died (P ¼0.88). Of the def-inite cases who died, three patients received levofloxacin and ninerifampicin (P ¼0.17). The cause of death was disease per se in 22(infarction and hydrocephalus), secondary infection in 9, aspir-ation in 3 and shunt complications in 2 patients.

Secondary outcome

The functional outcome at 6 months in the levofloxacin groupwas poor in 10 (21.3%), partial in 10 (21.3%) and complete in27 (57.4%) patients. In the rifampicin group, these values were5 (13.5%), 6 (16.2%) and 26 (70.3%) patients, respectively(P ¼0.47). At 6 months, a total of 36 patients died and in 20patients follow-up MRI was not conducted as their study drugwas withdrawn due to SAEs. Therefore, follow-up MRI studies

are available in 66 patients (33 in each group) only. The repeatMRI findings at 6 months did not reveal significant differencebetween the levofloxacin armand the rifampicin armwith respectto the appearance of new infarction (2 versus 3, P ¼0.64), appear-ance or enlargement of tuberculoma (18 versus 18, P ¼1.00),hydrocephalus (9 versus 7, P ¼0.57) or exudates (9 versus 5,P ¼0.23). The patients in the levofloxacin arm had a significantlyhigher frequency of seizures compared with the patients in therifampicin arm (15/60 versus 4/60, P ¼0.006). In the levofloxacinarm, three patients developed myoclonus and one patient devel-oped encephalopathy. Transaminase levels were insignificantlyhigher in the rifampicin group compared with the levofloxacingroup (178+270 versus 139+144 U/L, P ¼0.76) (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 thefirst weekin 11, the second week in 7, the third to fourth week in 4 and afterthe fourth week in 5 patients.

Discussion

In the present study, the survival of TBM patients at 6 months wassignificantly better in the levofloxacin arm compared with therifampicin arm, although the functional outcome was not signifi-cantly different. The role of fluoroquinolones in the treatment of tuberculosis has been evaluated mostly in pulmonary tubercu-losis.21,22 The efficacy of quinolones in TBM has been evaluatedin two studies only. In one study in 61 patients with TBM, the

role of ciprofloxacin, gatifloxacin and levofloxacin in addition tostandard ATT was compared. The CSF penetration was maximalfor levofloxacin followed by gatifloxacin and ciprofloxacin. Therewas a U-shaped response; the worst outcome was in the patientswith the lowest and the highest plasma and CSFquinolone expos-ure compared with those with intermediate quinolone expos-ure.23 We therefore chose 500 mg/day levofloxacin to optimizethe benefit based on its U-shaped response. Moreover, levofloxa-cin had to be withdrawn in 16 of our patients even at the dose of 500 mg/day due to seizure, myoclonus or encephalopathy. Thehigher incidence of seizures following levofloxacin in our studymay be due to more severe meningitis or a genetic susceptibility.

Table 1. Comparison of baseline clinical characteristics in patients with

TBM receiving levofloxacin or rifampicin

Parameter

Levofloxacin

(n¼60)

Rifampicin

(n¼60) P value

Age (years), mean+SD 39.3+16.5 38.0+18.5 0.42

Female 29 24 0.36

Duration of illness (weeks) 10.51+9.36 11.11+9.23 0.72

Diabetes 7 7 1.00

Hypertension 4 9 0.14

Ischaemic heart disease 3 0 0.08

GCS score 11.8+3.1 12.4+3.2 0.31

Focal weakness 24 22 0.85

Extra-CNS tuberculosis 14 16 0.67

HIV positive 1 3 0.31

Stage of TBM

I 9 12 0.70

II 33 33

III 18 15

Table 2. Laboratory and MRI findings in the patients with TBM receiving

levofloxacin or rifampicin

Parameter

Levofloxacin

(n¼60)

Rifampicin

(n¼60) P value

CSF

cells/mm3 183+217 313+822 0.96

protein (mg/dL) 192.4+166.5 196.7+167.9 0.75

glucose (mg/dL) 42.1+31.9 47.4+33.1 0.40

bacteriologically confirmeda 18 24 0.17

serum bilirubin (mg/dL) 1.2+1.5 0.92+0.98 0.23SGPT (U/L) 75+96 86+146 0.75

serum albumin (g/dL) 3.4+0.7 3.4+0.8 0.75

serum creatinine (mg/dL) 1.0+0.5 0.9+0.4 0.28

serum sodium (mEq/L) 132+8.0 134.0+8.0 0.15

MRI findings

abnormal 54 51 0.58

exudate 25 22 0.62

hydrocephalus 25 26 0.86

tuberculoma 27 25 0.77

infarction 26 26 1.00

SGPT, serum alanine transferase.a

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

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The seizurogenicpotential of quinolones has also been reported inearlier studies.24,25

MRI changes at 6 months were not significantly differentbetween the levofloxacin and rifampicin arms. Only five patientsdeveloped infarction at follow-up, which is much lowerthan in ourearlier reports in which 32%–40% of patients developed infarc-

tion after initiation of ATT.15,26,27

The lower frequency of infarctionin the present study may be due to the use of both corticosteroidand aspirin. We used a relatively lower dose of corticosteroid com-pared with the study from Vietnam in which 0.3–0.4 mg/kg dexa-methasone was used and tapered over 6–8 weeks. Long-termfollow-up revealed insignificantly higher survival at 2 years butnot at 5 years.28 In our earlier studies, we have used 10 mg/kgmethyl prednisolone intravenously for 5 days in TBM and it didnot result in improvement in clinical and in somatosensory andmotor evoked potentials compared with those who were not onmethylprednisolone.17,29 In the present study, therefore, weused 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 open-label design. A large number of patients could not be randomizeddue to seizure at presentation or already being on ATT. Moreover, inmany patients, levofloxacin had to be withdrawn due to SAEs. Itwould have been better to exclude the patients with structuralbrain 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 studyusing levofloxacin as an add-on antitubercular drugis in progress.30

From this study, it can be concluded that levofloxacin in TBMresults 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 rifampicinespecially in patients with hepatic dysfunction who do not have

seizure.

AcknowledgementsWe thank Mr Rakesh Kumar Nigam for secretarial help.

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

Transparency declarationsNone to declare.

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%) 0.14/0.07Functional 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%)

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

1.0

LevofloxacinRifampicin

0.9

0.8

0.7

0.6

Number at riskLevofloxacinRifampicin

6060

4842

4740

4738

4737

4737

4737

0 30 60 90

Time (days)

C u m u l a t i v e s u r v i v a l

120 150 180

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

Figure 2. Survival analysis using Cox regression shows cumulative survivalof the TBM patients receiving levofloxacin and rifampicin after adjustmentfor covariates.

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

levofloxacin or rifampicin

Side effect

Levofloxacin

(n¼

60)

Rifampicin

(n¼

60) P value

Seizure 15 4 0.006

Myoclonus 3 0 0.08

Encephalopathy 1 0 0.32

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

SGPT, serum alanine transferase.aHighest values during the study period.

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Author contributions

J. K. was involved in protocol design, randomization, data analysis andwriting the manuscript, U. K. M. was involved in planning the study andwriting 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.

References1 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. JAMA1999; 282: 677–86.

2 Kalita J, Misra UK, Ranjan P. Predictors of long-term neurologicalsequelae of tuberculous meningitis: a multivariate analysis. Eur J Neurol2007; 14: 33–7.

3 Thwaites GE. The diagnosis and management of tuberculousmeningitis. Practical Neurology 2002; 2: 250–61.

4 Ellard GA, Humphries MJ, Allen BW. Cerebrospinal fluid drugconcentrations and the treatment of tuberculous meningitis. Am Rev

Respir Dis 1993; 148: 650–5.5 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 variouscompartments of the human brain: a novel method for determining druglevels in the cerebral extracellular space. Antimicrob Agents Chemother 1998; 42: 2626–9.

7 Cheng IK, Chan PC, Chan MK. Tuberculous peritonitis complicatinglong-term peritoneal dialysis. Report of 5 cases and review of theliterature. 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: 246–7.

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 drugresistance on response to treatment and outcome in adults withtuberculous meningitis. J Infect Dis 2005; 192: 79–88.

11 Ruslami R, Ganiem AR, Dian S et al. Intensified regimen containingrifampicin and moxifloxacin for tuberculous meningitis: an open-label,randomised controlled phase 2 trial. Lancet Infect Dis 2013; 13: 27–35.

12 Parthasarathy R, Sarma GR, Janardhanam B etal. Hepatic toxicity in SouthIndian patients during treatment of tuberculosis with short-course regimenscontaining isoniazid, rifampicinand pyrazinamide.Tubercle 1986; 67: 99–108.

13 Mehta S. Malnutrition and drugs: clinical implications. Dev PharmacolTher 1990; 15: 159–65.

14 Yew WW, Chan CK, Leung CC et al. Comparative roles of levofloxacinand ofloxacin in the treatment of multidrug-resistant tuberculosis:

preliminary results of a retrospective study from Hong Kong. Chest 2003;124: 1476–81.

15 Misra UK, Kalita J, Nair PP. Role of aspirin in tuberculous meningitis: arandomized open label placebo controlled trial. J Neurol Sci 2010;293: 12–7.

16 Patel VB, Padayatchi N, Bhigjee AI e t a l. Multidrug-resistanttuberculous meningitis in KwaZulu-Natal, South Africa. Clin Infect Dis2004; 38: 851–6.

17 Misra UK, Kalita J, Roy AK et al. Role of clinical, radiological, andneurophysiological changes in predicting the outcome of tuberculousmeningitis: a multivariable analysis. J Neurol Neurosurg Psychiatry 2000;68: 300–3.

18 British Medical Research Council. Streptomycin in tuberculosis trialscommittee: streptomycin treatment of tuberculous meningitis. Lancet1948; 1: 582–96.

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-inducedhepatotoxicity. Am J Respir Crit Care Med 1998; 157: 1871–6.

21 TahaogluK, Torun T,SevimT etal. The treatment of multidrug-resistanttuberculosis in Turkey. N Engl J Med 2001; 345: 170–4.

22 Richeldi L, Covi M, Ferrara G et al. Clinical use of levofloxacin in thelong-term treatment of drug resistant tuberculosis. Monaldi Arch ChestDis 2002; 57: 39–43.

23 Thwaites GE, Bhavnani SM, Chau TT et al. Randomized pharma-cokinetic and pharmacodynamic comparison of fluoroquinolonesfor tuberculous meningitis. Antimicrob Agents Chemother 2011; 55:3244–53.

24 Bellon A, Perez-Garcia G, Coverdale JH et al. Seizures associated withlevofloxacin: case presentation and literature review. Eur J ClinPharmacol 2009; 65: 959–62.

25 Misra UK,KalitaJ, Chandra S etal. Association of antibiotics with statusepilepticus. Neurol Sci 2013; 34: 327–31.

26 Kalita J, Prasad S, Maurya PK et al. MR angiography in tuberculousmeningitis. Acta Radiol 2012; 53: 324–9.

27 Kalita J, Misra UK,Nair PP. Predictors of stroke andits significance in theoutcome of tuberculous meningitis. J Stroke Cerebrovasc Dis 2009;18: 251–8.

28 Torok ME, Nguyen DB, Tran TH et al. Dexamethasone and long-termoutcome of tuberculous meningitis in Vietnamese adults andadolescents. PLoS One 2011; 6: e27821.

29 Kalita J, Misra UK. Effect of methyl prednisolone on sensory motorfunctions in tuberculous meningitis. Neurol India 2001; 49: 267–71.

30 HeemskerkD, DayJ, Chau TTetal. Intensified treatment withhigh doserifampicin and levofloxacin compared to standard treatment for adultpatients with tuberculous meningitis (TBM-IT): protocol for a randomizedcontrolled trial. Trials 2011; 2: 12 25.

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