EFFECTIVENESS OF MOXIFLOXACIN IN THE MANAGEMENT OF TUBERCULOUS MENINGITIS: A PILOT STUDY.
Objective: To determine the effectiveness of moxifloxacin as fourth drug in the management of tuberculous meningitis (TBM).
Methodology: This hospital based comparative clinical trial was done as pilot study from January 2016 to December 2017. The study was carried out on 43 patients with TBM. Moxifloxacin based regimen (group I) versus standard treatment for tuberculous meningitis (group II) were compared. Computer software, SPSS version 21.0, was used for data entry and analysis. Statistical significance was considered at p value <0.05.
Results: Out of 43 patients, there were 15 (34.9%) males and 28 (65.1%) females. Age of the patients ranged from 13 to 80 years (mean 31.418 +-18.62 years). Fever, headache, vomiting and altered level of consciousness was present in 38 (88.4%); neck stiffness in 39 (90.69%) and neurological deficit was present in 18 (41.9%) patients. Leptomeningeal enhancement was the most frequent radiological finding found in 13 (30.2%) patients. Overall improvement occured in 38 (88.37%) of patients. In group I, 21/22 (95.45%) patients and in group II, 17/21 (80.95%) patients improved, (p value 0. 158). Till 3rd day of commencement of treatment, 11/21 (52.38%) patients recovered in group I while 02/17 (11.76%) patients recovered in group II.
Conclusion: Moxifloxacin based regimen was associated with an early recovery (within 03 days of commencement of treatment) in a significant number of patients with TBM.
KeyWords: Tuberculous meningitis, Treatment regimens, Fluoroquinolones, Moxifloxacin.
Tuberculosis (TB) continues to be a global health issue with 1.5 million deaths annually. It is highly prevalent in third world countries including PakistanA1.Tuberculous involvement of the central nervous system (CNS) represents about 1% of all new cases annuallyA2. Tuberculous meningitis (TBM) is the subset of CNS TB and occurs in 4% cases of CNS TBA3. It has a poor outcome with significant morbidity (hemiparesis, cranial nerve palsies and persistent vegetative states) and mortality in approximately 50% of its victims4.
The spectrum of TBM includes meningitis or meningo-encephalitis, hydrocephalus, tuberculomas and cerebral vasculitis5,6. The clinical presentation ranges from headache, cranial nerve palsies, seizures to stupor and coma. Neck stiffness is an important clinical clue towards the diagnosis. Currently, TBM is treated in the line of pulmonary TB with standard first-line drugs (combination of isoniazid, rifampin, pyrazinamide, ethambutol) and cortico-steroids are added. A prolonged treatment duration of 9-12 months is recommended due to the serious risk of morbidity and mortality associated with TBM7. However, concerns are raised over the lack of evidence supporting the longer treatment duration for TBM8,9 and whether same anti-TB drugs will be similarly suitable and successful in the treatment of TBM4. Replacement of ethambutol by streptomycin is recommended by World Health Organization (WHO) because of the ineffective cerebrospinal fluid (CSF) penetration of ethambutol7.
Furthermore, ethambutol is not given in obtunded patients and in children as these are unable to report the possible visual complications inherently associated with TBM per se or ethambutol use. On the other hand, streptomycin did not show good CSF penetration in the absence of inflammation10 and serious adverse events like nephrotoxicity and ototoxicity are associated with it. Ototoxicity may be confused with underlying disease process. Moreover, streptomycin is given through intra-muscular injections which is painful and health care professional is required to inject it and therefore may result in decreased compliance11. These side effects of ethambutol or streptomycin are of concern in patients with TBM, as they cannot report their symptoms due to blurred sensorium; and are measurable only in clinically alert and communicating patient.
The newer generation uoroquinolones, have shown excellent CSF penetration, safety profiles and strong activity against Mycobacterium tuberculosis. For these reasons, uoroquinolones may be considered to have great potential for incorporation in TBM treatment regimens and good alternatives to ethambutol or streptomycin. Among the uoroquinolones, moxifloxacin is found to have greatest in vitro and in vivo activity against M. tuberculosis, good penetration into the CSF, is relatively safe and better tolerated12-14. We, therefore, used moxifloxacin as fourth drug (replacing ethambutol or streptomycin) in the initial 02 months of intensive phase management of tuberculous meningitis in our study. The purpose of the current research was to determine the effectiveness of moxifloxacin as fourth drug in the management of TBM.
It may help in providing the scientific basis and recommendations regarding the alternative regimens for TBM and may help in reducing the optic, otological and neurological disabilities associated with prior regimens of TBM.
This hospital based comparative clinical trial was conducted as pilot study from January 2016 to December 2017. The study was carried out on 43 patients with TBM, who presented to the Department of Medicine, Lady Reading Hospital, Medical Teaching Institution, Peshawar. Patients of either gender, above 12 years of age with clinical, CSF and radiological features suggestive of TBM were included in the study. Exclusion criteria were known hypersensitivity to moxifloxacin; baseline serum alanine amino-transferase (ALT) level more than 05 times the upper limit of normal; pregnancy; failure to obtain CSF for analysis via diagnostic lumbar puncture; evidence of acute bacterial or viral meningitis; and those unwilling to participate or give informed consent. These factors would have influenced the study results and might lead to confounding and bias in the study. As this was a pilot study, so sample size was not calculated but 30 patients were considered as minimum for the study.
The study participants (n=43) were randomized by lottery/draw method to either group I (moxifloxacin based regimen;n=22) or group II (standard treatment regimen; n=21). Patients were selected by non-probability convenient sampling method. Operational diagnosis of TBM was based on the presence of a meningeal syndrome and typical CSF picture. It was supported by the neuro-imaging findings. Meningeal syndrome (meningitis or meningo-encephalitis) was defined as onset of illness of more than one week; low grade fever, headache, vomiting, confusion, seizures, altered level of consciousness, neck stiffness, hemiparesis and cranial nerve palsies. Typical CSF picture for TBM was defined as lymphocytic pleocytosis (increased number of cells which are predominantly lymphocytes), elevated protein and low CSF glucose concentration.
Supportive findings on contrast enhanced neuro-imaging i.e. cerebral computed tomography (CT brain) and cerebral magnetic resonance imaging (MRI brain) include: leptomeningeal enhancement, tuberculomas, hydrocephalus, vasculitis and cerebral infarctions. Ethical approval for the research was obtained from the Institutional Review Board (IRB) of the hospital. The purpose of our research was discussed with the patients or their close relatives. They were briefed that their rights will be taken into consideration and the information obtained will be solely used for research purpose. Confidentiality was assured and then an informed written consent in Urdu language was taken from the patients or their close relatives depending on the level of consciousness of the patients and the ability to give consent.
Patients meeting the inclusion criteria were admitted through the Emergency Department to the Medical Units of Lady Reading Hospital, Medical Teaching Institution, Peshawar. All patients were assessed clinically. A structured questionnaire covering demographics (age, sex, address, marital status, occupation, socioeconomic status and past or family history of tuberculosis) was utilized. They were thoroughly asked about pertinent presenting features (low grade fever, headache, vomiting, confusion, seizures, altered level of consciousness) and duration of illness. Focused clinical examination for presence of neurological deficit (neck stiffness, hemiparesis and cranial nerve palsies) was performed. Level of consciousness was assessed by Glasgow Coma Scale (GCS). Ocular examination was performed for pupillary changes and papilledema.
The neurological status of patients with TBM was graded according to the modified British Medical Research Council (BMRC) grading system as grade 1 (GCS score 15 but with no focal neurological signs); grade 2 (GCS score 15 and presence of focal neurological signs or GCS score 11-14) and grade 3 (GCS score <10)15. Typical CSF picture for TBM was defined as lymphocytic pleocytosis, elevated protein and low CSF glucose concentration. Supportive findings on contrast enhanced neuro-imaging i.e. cerebral computed tomography (CT brain) and cerebral magnetic resonance imaging (MRI brain) include: leptomeningeal enhancement, tuberculomas, hydrocephalus, vasculitis and cerebral infarctions. Lumbar puncture was performed for CSF examination and analysis. Naked eye examination of CSF sample was done for appearance and any web formation. Opening pressure was measured at bedside. The collected CSF samples were then sent to the hospital lab for cytology, chemistry and staining (Gram, ZN staining).
Contrast-enhanced neuro-imaging (CT scan and/or MRI brain) were performed for the diagnosis and assessment of complications of TBM (lepto-meningeal enhancement, hydrocephalus, tuberculomas or evidence of cerebral vasculitis/infarcts). Relevant investigations including complete blood count, blood glucose level, serum ALT, chest x-ray and 12-lead electrocardiogram (ECG), were carried out at Lady Reading Hospital, Peshawar. We compared moxifloxacin based regimen (combination of isoniazid, rifampin, pyrazinamide, moxifloxacin) with standard treatment (combination of isoniazid, rifampin, pyrazinamide, ethambutol) for TBM. Cortico-steroid (dexamethasone) was given to both groups accordingly. All anti-TB drugs were given in standard doses and moxifloxacin was given in 400 mg daily dose. All oral drugs were given once daily before breakfast. Those who could not swallow, drugs were given per nasogastric (NG) tube. Adherence was directly monitored by the researcher.
Patients were observed and the effectiveness was calculated in terms of symptoms resolution, improvement in GCS score or neurological deficit. In selected cases neuro-imaging was repeated to look for reduction in lepto-meningeal enhancement or in number / size of tuberculomas and decrease in hydrocephalus. The day of recovery was recorded in patients in both groups. The collected data were entered into a predesigned proforma. Computer software, SPSS version 21.0, was used for data analysis. For numerical variables (age, GCS score and day of recovery), mean +-SD was calculated; while for categorical variables (gender, clinical presentation and imaging features), frequencies and percentages were calculated. Improvement was compared between the two groups using chi square test. Statistical significance was considered at p value a$?0.05. All results were presented as tables.
Table 1: Neurological deficit in patients with TBM (n=43).
Cranial Nerve Palsies###5###11.6
No Neurological Deficit###25###58.1
Table 2: Radiological findings in patients with TBM (n=43)
Leptomeningeal Enhancement Only###13###30.2
Leptomeningeal Enhancement +###2###4.7
Hydrocephalus + Infarct
Tuberculomas + Infarcts###1###2.3
Table 3: Neurological status of TBM patients in the 02 treatment groups (n=43)
BMRC Grade of###Drug Regimen###Total
Neurological Status###Moxifloxacin Based###Standard Treatment
###Regimen(Group I)###Regimen(Group II)
Table 4: Improvement of patients in the 02 treatment groups (n=43)
Improvement###Drug Regimen###Total###P value
###Moxifloxacin Based###Standard Treatment
###Regimen(Group I)###Regimen(Group II)
Table 5: Recovery day in both groups (n=38
Neurological Deficit###Drug Regimen
###Moxifloxacin Based###Standard Treatment
###Regimen(Group I)###Regimen(Group II)
There were 43 patients of TBM in the present study. Among them, there were 15 (34.9%) males and 28 (65.1%) females. Male to female ratio was 1:1.86. Age of the patients ranged from 13 to 80 years with mean age of 31.418 +-18.62 years. It was more common in younger age group; 48.8% in <20 years of age and 76.7% in 8-10 and AUC/MIC ratios of >100-125 (where Cmax =peak serum concentration, AUC =24-hour area-under-the-curve and MIC =minimum inhibitory concentration). Based on these parameters, moxifloxacin was considered as the most active fluoroquinolone against tuberculosis at the usual recommended dose of 400 mg daily30. However, interactions with other drugs may alter its pharmacokinetic properties31,32.
Rifampicin if given together with moxifloxacin may lead to 31% decreased plasma concentrations of moxifloxacin. However, the relevance of this interaction in clinical practice is unclear33, because another research showed that increasing the dose of rifampicin and moxifloxacin were not associated with increased toxicity34. In an Indonesian randomized trial, higher intravenous dose of rifampicin in combination with moxifloxacin was used. More than 50% reduction in mortality was reported10. They argued that increasing the dose leads to higher availability of rifampicin in blood and CSF by a factor of 3 with resultant increased therapeutic response35. On the other hand, a trial in Vietnam compared the standard regimen for TBM with an intensified treatment regimen comprising of higher dose rifampicin and levofloxacin in adult patients with TBM. It was found that the latter regimen was not associated with improved survival or other treatment benefits36.
However, it was suggested that the lack of therapeutic benefits may be due to the "not high enough" chosen dose of rifampicin. Moreover, it was given orally and not intravenously, as in the study by Ruslami et al10. In the study by Thwaites et al38, fluoroquinolones were found to add anti-TB activity to the existing standard treatment regimen. However, it was stressed that these need to be instituted early in the management of TBM for improved outcomes.
Our study has several limitations. This study was conducted in a single center. It is essential for better policy making to observe the data from multiple centers with larger samples and for a longer time period. Moxifloxacin exhibits extensive inter-individual pharmacokinetic variability. Moreover, rifampicin may have interaction with moxifloxacin and thus higher dose of moxifloxacin may be needed which was not used in the current study. Serial lumbar punctures for cerebrospinal fluid analysis and repeat neuroimaging were not done, so biochemical and radiological response could not be documented.
There was no statistically significant difference between the moxifloxacin based regimen and conventional regimen regarding improvement in patients with TBM. However, moxifloxacin based regimen was associated with an early recovery (within 03 days of commencement of treatment) in a significant number of patients with TBM.
Moxifloxacin can be considered as a valuable addition to the existing therapeutic armamentarium of TBM management. It, therefore, can be considered as an attractive alternative option in TBM treatment. However, further research and larger scale studies are needed to devise optimum regimens against M. tuberculosis.
1. World Health Organization. Global tuberculosis report. Geneva: WHO; 2014. Available at: http://www. who.int/tb/publications/global_report/gtbr14_executive_summary.pdf
2. Phypers M, Harris T, Power C. CNS tuberculosis: a longitudinal analysis of epidemiological and clinical features. Int J Tuberc Lung Dis 2006; 10:99-103.
3. Abdelmalek R, Kanoun F, Kilani B, Tiouiri H, Zouiten F, Ghoubantini A et al. Tuberculous meningitis in adults: MRI contribution to the diagnosis in 29 patients. Int J Infect Dis 2006; 10:372-7.
4. Hoang Mai NT, Thwaites GE. The current pharmacological landscape of tuberculous meningitis: where to next? Expert Rev Clin Pharmacol 2016; 9:625-7.
5. Thwaites GE, Van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol 2013; 12:999-1010.
6. Tai MLS. Tuberculous meningitis: diagnostic and radiological features, pathogenesis and biomarkers. Neuro sci Med 2013; 4: 101-7.
7. World Health Organization. Guidelines for treatment of tuberculosis (4th ed). WHO; 2010:147. Available at: http://www.who.int/tb/publications/2010/9789241547833/en/
8. Donald PR. The chemotherapy of tuberculous meningitis in children and adults. Tuberculosis (Edinb) 2010; 90:375-92.
9. Ellard GA, Humphries MJ, Allen BW. Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis. Am Rev Respir Dis 1993; 148:650-5.
10. Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomized controlled phase 2 trial. Lancet Infect Dis 2013; 13:27-35.
11. Lolachi S, Janssens JP, Adler DL. Tuberculous meningitis, what's new? J Neuro infect Dis 2017; 8:2.
12. Lubasch A, Keller I, Borner K, Koeppe P, Lode H. Comparative pharmacokinetics of ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, trovafloxacin, and moxifloxacin after single oral administration in healthy volunteers. Antimicrob Agents Chemother 2000; 44:2600-3.
13. Shandil RK, Jayaram R, Kaur P, Gaonkar S, Suresh BL, Mahesh BN et al. Moxifloxacin, ofloxacin, sparfloxacin, and ciprofloxacin against Mycobacterium tuberculosis: evaluation of in vitro and pharmacodynamic indices that best predict in vivo efficacy. Antimicrob Agents Chemother 2007; 51:576-82.
14. Burman WJ, Goldberg S, Johnson JL, Muzanye G, Engle M, Mosher AW et al. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 2006; 174:331-8.
15. Almeida D, Nuermberger E, Tyagi S, Bishai WR, Grosset J. In vivo validation of the mutant selection window hypothesis with moxifloxacin in a murine model of tuberculosis. Antimicrob Agents Chemother 2007; 51: 4261-6.
16. Van TTT, Farrar J. Tuberculous meningitis 2014; 68:2-3. Available at: http://www.uptodate.com/contents/central-nervous-system-tuberculosis
17. Wasay M, Farooq S, Khowaja ZA, Bawa ZA, Ali SM et al. Cerebral infarction and tuberculoma in central nervous system tuberculosis: frequency and prognostic implications. J Neurol Neurosurg Psychiatry 2014; 85:1260-4.
18. Sheu JJ, Yuan RY, Yang CC. Predictors for outcome and treatment delay in patients with tuberculous meningitis. Am J Med Sci 2009; 338:134-9.
19. Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med 2014; 371:1577-87.
20. Spigelman MK. New tuberculosis therapeutics: a growing pipeline. J Infect Dis 2007; 196:S28-34.
21. Takiff H, Guerrero E. Current prospects for the fluoroquinolones as first-line tuberculosis therapy. Antimicrob Agents Chemother 2011; 551:5421-9.
22. Fouad M, Gallagher JC. Moxifloxacin as an alternative or additive therapy for treatment of pulmonary tuberculosis. Ann Pharmacother 2011; 45:1439-44.
23. Kanellakopoulou K, Pagoulatou A, Stroumpoulis K, Vafiadou M, Kranidioti H, Giamarellou H et al. Pharmacokinetics of moxifloxacin in non-inflamed cerebrospinal fluid of humans: implication for a bactericidal effect. J Antimicrob Chemother 2008; 61:1328-31.
24. Alffenaar JW, van Altena R, Bokkerink HJ, Luijckx GJ, van Soolingen D, Aanoutse RE et al. Pharmacokinetics of moxifloxacin in cerebrospinal fluid and plasma in patients with tuberculous meningitis. Clin Infect Dis 2009; 49:1080-2.
25. Ostergaard, C, Sorensen TK, Knudsen JD, Fri-modt-Moller N. Evaluation of moxifloxacin, a new 8-methoxyquinolone, for treatment of meningitis caused by a penicillin-resistant pneumococcus in rabbits. Antimicrob Agents Chemother 1998; 42:1706-12.
26. Rodriguez-Cerrato V, McCoig CC, Michelow IC, Ghaffar F, Jafri HS, Hardy RD et al. Pharmacodynamics and bactericidal activity of moxifloxacin in experimental Escherichia coli meningitis. Antimicrob Agents Chemother 2001; 45:3092-7.
27. Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC et al. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomized, controlled phase II trial. Lancet 2009; 373:1183-9.
28. Rodriguez JC, Ruiz M, Climent A, Royo G. In vitro activity of four fluoroquinolones against Mycobacterium tuberculosis. Int J Antimicrob Agents 2001; 17:229-31.
29. Alffenaar JW, de Vries PM, Luijckx GJ, van Soolingen D, van der Werf TS, van Altena R. Plasma and cerebrospinal fluid pharmacokinetics of moxifloxacin in a patient with tuberculous meningitis. Antimicrob Agents Chemother 2008; 52:2293-5.
30. Ginsburg AS, Grosset JH, Bishai WR. Fluoroquinolones, tuberculosis and resistance. Lancet Infect Dis 2003; 3:432-42.
31. Nijland HM, Ruslami R, Suroto AJ, Burger DM, Alisjahbana B, van Crevel R et al. Rifampicin reduces plasma concentrations of moxifloxacin in patients with tuberculosis. Clin Infect Dis 2007; 45:1001-7.
32. Weiner M, Burman W, Luo CC, Peloquin CA, Engle M, Goldberg S et al. Effects of rifampin and multidrug resistance gene polymorphism on concentrations of moxifloxacin. Antimicrob Agents Chemother 2007; 51:2861-6.
33. Naidoo A, Naidoo K, Mcllleron H, Essack S, Padayatchi N. A Review of Moxifloxacin for the Treatment of Drug-Susceptible Tuberculosis. J Clin Pharmacol 2017; 57:1369-86.
34. Donald PR. Chemotherapy for Tuberculous Meningitis. N Engl J Med 2016; 374:179-81.
35. Te Brake L, Dian S, Ganiem AR, Ruesen C, Burger D, Donders R et al. Pharmacokinetic/ pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis. Int J Antimicrob Agents 2015; 45:496-503.
36. Heemskerk AD, Bang ND, Mai NT, et al. Intensified antituberculosis therapy in adults with tuberculous meningitis. N Engl J Med 2016; 374:124-4.
37. Thwaites GE, Bhavnani SM, Chau TT, Hammel JP, Torok ME, Van Wart SA et al. Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis. Antimicrob Agents Chemother 2011; 55:3244-53.
|Printer friendly Cite/link Email Feedback|
|Publication:||Journal of Postgraduate Medical Institute|
|Date:||Jun 30, 2018|
|Previous Article:||A PATIENT WITH MUCORMYCOSIS AND ASPERGILLOSIS: CASE REPORT.|
|Next Article:||EFFECTIVENESS AND SAFETY OF ENOXAPARIN AS ANTICOAGULANT IN PATIENTS UNDERGOING ELECTIVE PERCUTANEOUS CORONARY INTERVENTION FOR STABLE CORONARY ARTERY...|