Elsevier

Tuberculosis

Volume 98, May 2016, Pages 1-6
Tuberculosis

Diagnostics
Safety and efficacy of additional levofloxacin in tuberculous meningitis: A randomized controlled pilot study

https://doi.org/10.1016/j.tube.2016.01.004Get rights and content

Summary

Background

Levofloxacin is an effective bactericidal category III antitubercular drug. There is paucity of studies comparing the role of additional levofloxacin to standard antitubercular regimen in the patients with tuberculous meningitis (TBM).

Aims

To compare the safety and efficacy of adding levofloxacin to standard four drug ATT regimen (RHZE).

Subjects and methods

The patients with TBM diagnosed on the basis of clinical, cerebrospinal fluid (CSF) and MRI criteria were included. Children below 15 years, patients with pregnancy, seizures, liver failure, kidney failure and malignancy were excluded. The baseline clinical, CSF and MRI characteristics were noted and consciousness was evaluated by Glasgow Coma Scale (GCS). The patients were randomized to RHZE (rifampicin, isoniazid, pyrazinamide and ethambutol) and RHZEL (RHZE and levofloxacin) groups. Outcome was defined at 6 months. Primary outcome was death and secondary outcomes were disability as assess by Barthel Index score and adverse events.

Results

Out of 110 TBM patients screened, 57 fulfilled the inclusion criteria. Their median age was 35 (15–75) years. 29 patients received RHZEL and 28 RHZE. The baseline clinical, biochemical and MRI characteristics were similar in the two groups. At 6 months, 11 (19.3%) patients died, 38 (66.7%) had good and 7 (12.3%) poor outcome. There was insignificant survival benefit in RHZEL group compared to RHZE (HR-2.61, 95% CI 0.73–9.36, P = 0.14), 25% patients died in RHZE where as 13.8% in RHZEL group. The disability was not significantly different between the two groups. The composite side effects were also similar between the two groups except for a higher frequency of seizure in RHZEL group (5 Vs 0) which resulted in withdrawal of levofloxacin.

Conclusion

There was insignificant survival benefit in RHZEL which was associated with high frequency of seizures.

Introduction

The prevalence of tuberculosis in the world is 159/100,000 population and one-third of these patients reside in India and China [1]. One-tenth of patients with extrapulmonary tuberculosis have central nervous system (CNS) involvement which is the most severe form of tuberculosis resulting in high mortality and morbidity [2]. Treatment of CNS tuberculosis is based on the experience of pulmonary tuberculosis but has special issues because of poor cerebrospinal fluid (CSF) penetration of some of the 1st line antitubercular drugs. Amongst the recommended category I drugs such as isoniazid (INH), rifampicin, pyrazinamide and ethambutol, rifampicin has poor CSF penetration and ethambutol penetrates into the CSF only when meninges are inflamed [3], [4], [5]. Moreover ethambutol is bacteriostatic. The choice of antitubercular drugs in CNS tuberculosis should have the following features – 1) good CSF penetration, 2) bactericidal activity, 3) least side effects; 4) minimal or no drug interactions, and 5) regional prevalence of multidrug resistant (MDR) tuberculosis. In 2013, there were 300,000 cases of MDR tuberculosis and more than 50% of them were from India, China and Russia [1]. Quinolones although have been categorized as category III antitubercular drugs, but are bactericidal, safe for liver and kidney, have minimal drug interaction and have good CSF penetration. Quinolones are effective in MDR tuberculosis [6], [7], [8], [9]. In a randomized controlled trial on tuberculous meningitis (TBM), levofloxacin resulted in better 6 months survival compared to rifampicin [10]. In this study, rifampicin was compared with levofloxacin in addition to INH, ethambutol and pyrazinamide. In a recent randomized controlled trial, standard RHZE (rifampicin, isoniazid, pyrazinamide, ethambutol) regimen was compared with intensive regimen in which rifampicin was given in a dose of 15 mg/kg and levofloxacin 20 mg/kg for initial 8 weeks followed by standard treatment. At the end of 9 months there was no difference in mortality and disability [11]. In this trial, two regimens were compared rather than the individual drug. There is no study comparing standard antitubercular regimen RHZE to the regimen with additional levofloxacin (RHZEL). In this communication, we report the efficacy and safety of RHZEL and compare it with RHZE in the patients with TBM.

Section snippets

Study design

This is an open labeled randomized controlled pilot study comparing RHZE versus RHZEL. The study was conducted in a tertiary care teaching hospital in India during February 2013 and March 2015. The trial was approved by Institute Ethics Committee. The patients or their caregiver gave informed consent. This is an investigator initiated trial and the protocol was designed by UK and JK.

Sample size calculation

The sample size was calculated keeping the type I error α = 0.05 and type II error β = 0.15 using Fisher exact

Results

110 patients were screened and 53 of them were excluded because of seizure in 29 and liver dysfunction in 7 patients (Figure 1). The results therefore are based on 57 patients with TBM. The median age of the patients was 35 (15–75) years and 27 were females. The majority of the patients were in stage II (40) and stage III (13) meningitis. The median duration of illness was 43 (15–180) days. Focal weakness was present in 27 patients; hemiplegia in 18, paraplegia in 6 and quadriplegia in 3

Discussion

This preliminary study shows insignificant survival benefit at 6 months by addition of levofloxacin to standard RHZE regimen in TBM. This benefit was at the cost of seizures resulting in drug withdrawal in 17.2% patients. This is the first study evaluating the role of additional levofloxacin for 6 months compared to standard antitubercular regimen in TBM. A recent randomized controlled trial however did not reveal any benefit in reducing mortality or disability using intensive higher dose of

Acknowledgment

We thank Dr SK Mandal, Statistician, Center of Biomedical research for statistical analysis and Mr. Rakesh Kumar Nigam for secretarial help.

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