Intensified Antituberculosis Therapy Regimen Containing Higher Dose Rifampin for Tuberculous Meningitis: A Systematic Review and Meta-Analysis

Abstract

Background: Tuberculous meningitis is difficult to diagnose and is associated with high mortality. Recently, several studies evaluated the intensified regimen containing higher dose rifampin to treat tuberculous meningitis. However, this topic remains to be concluded. Therefore, this systematic review and meta-analysis was conducted to evaluate pharmacokinetics parameters, safety, and survival benefits of high-dose rifampin for tuberculous meningitis.

Method: Data were searched from PubMed, EMBASE, The Cochrane Library, and Web of Science for studies describing an antituberculosis regimen including a higher dose of rifampin for patients with tuberculous meningitis. The quality of eligible studies was evaluated via The Cochrane Risk of Bias Tool. The meta-analysis was performed by Review Manager 5.3 software, the synthesis of the data was shown in mean difference (MD) or relative risk (RR), and 95% confidence intervals (CIs).

Results: There were six randomized control trails included in this meta-analysis. The results showed that the concentration in plasma and cerebrospinal fluid (CSF) were significantly higher in the intervention group than the standard group [MD = 22.08, 95%CI (16.24, 27.92), p < 0.00001; MD = 0.74, 95%CI (0.42, 1.05), p < 0.00001], as well as the area under the time concentration curve between 0 and 24 h (AUC_0-24) of rifampin [MD 203.56, 95%CI (153.07, 254.05), p < 0.00001] in plasma, but the overall survival did not improve [RR = 0.92, 95%CI (0.67, 1.26), p = 0.61]. For adverse events, the results showed a statistically significant lower incidence of hypersensitivity compared with the intervention group [RR = 1.72, 95%CI (1.13, 2.62), p = 0.01]. Fortunately, other common adverse drug reactions such as liver injury, neurological events, myelosuppression, and cardiotoxicity had no significant increase [RR = 0.98, 95%CI (0.77, 1.26), p = 0.90; RR = 1.10, 95%CI (0.94, 1.30), p = 0.23; RR = 0.82, 95%CI (0.59, 1.13), p = 0.22; RR = 1.11, 95%CI (0.66, 1.86), p = 0.70].

Conclusion: This meta-analysis suggested that the intensified treatment regimen including a higher dose of rifampin significantly increased the rifampin concentration both in the plasma and CSF, and it was safe in patients with tuberculous meningitis, but resulted in no improvement in survival rates.

Keywords: high-dose rifampin; meta-analysis; pharmacokinetics parameters; survival; tuberculous meningitis.

Figure 1

Flow diagram of studies.

Figure 2

Quality assessment of the studies. (A) Risk of bias summary: Review authors' judgements about each risk of bias item for each included study; (B) risk of bias graph: Review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3

Forest plot result of the maximum concentration of rifampin in plasma.

Figure 4

Forest plot result of the AUC0-24 of rifampin.

Figure 5

Forest plot results of the concentration of rifampin in CSF. (A) The result in the first 3 days; (B) the result at day 14.

Figure 6

Forest plot result of mortality.

Figure 7

Forest plot results of the occurrence of adverse events. (A) The result of liver injury; (B) the result of hypersensitivity; (C) the result of neurological events; (D) the result of myelosuppression; (E) the result of cardiologic events.