Rovina Ruslami

Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial.

BACKGROUND Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. METHODS In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755. FINDINGS 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC(0-6); 78·7 mg.h/L [95% CI 71·0-87·3] vs 26·0 mg.h/L [19·0-35·6]), maximum plasma concentrations (C(max); 22·1 mg/L [19·9-24·6] vs 6·3 mg/L [4·9-8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46-0·78] vs 0·21 mg/L [0·16-0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC(0-6) (31·5 mg.h/L [24·1-41·1] vs 15·1 mg.h/L [12·8-17·7]), C(max) (7·4 mg/L [5·6-9·6] vs 3·9 mg/L [3·2-4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81-3·27] vs 1·52 mg/L [1·28-1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20-0·91; p=0·03). INTERPRETATION These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. FUNDING Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.

Exposure to Rifampicin Is Strongly Reduced in Patients with Tuberculosis and Type 2 Diabetes

BACKGROUND Type 2 diabetes (DM) is a strong risk factor for tuberculosis (TB) and is associated with a slower response to TB treatment and a higher mortality rate. Because lower concentrations of anti-TB drugs may be a contributing factor, we compared the pharmacokinetics of rifampicin in patients with TB, with and without DM. METHODS Seventeen adult Indonesian patients with TB and DM and 17 age- and sex-matched patients with TB and without DM were included in the study during the continuation phase of TB treatment. All patients received 450 mg of rifampicin (10 mg/kg) and 600 mg of isoniazid 3 times weekly. Steady-state plasma concentrations of rifampicin and its metabolite desacetylrifampicin were assessed at 0, 2, 4, and 6 h after drug intake. RESULTS Geometric means of rifampicin exposure (AUC(0-6 h)) were 12.3 mg x h/L (95% confidence interval [CI], 8.0-24.2) in patients with TB and DM, and 25.9 mg x h/L (95% CI, 21.4-40.2) in patients with TB only (P=.003). Similar differences were found for the maximum concentration of rifampicin. No significant differences in time to maximum concentration of rifampicin were observed. The AUC(0-6 h) of desacetylrifampicin was also much lower in patients with TB and DM versus patients with TB only (geometric mean, 0.60 vs. 3.2 mg x h/L; P=.001). Linear regression analysis revealed that higher body weight (P<.001), the presence of DM (P=.06), and plasma glucose concentration (P=.016) were correlated with exposure to rifampicin. CONCLUSION Exposure (AUC(0-6 h)) to rifampicin was 53% lower in Indonesian patients with TB and DM, compared with patients with TB only. Patients with TB and DM who have a higher body weight may need a higher dose of rifampicin.

Rifampicin Reduces Plasma Concentrations of Moxifloxacin in Patients with Tuberculosis

BACKGROUND The long duration of the current tuberculosis (TB) treatment is demanding and warrants the development of new drugs. Moxifloxacin shows promising results and may be combined with rifampicin to shorten the duration of TB treatment. Rifampicin induces the phase II metabolic enzymes that are involved in the biotransformation of moxifloxacin. Therefore, the interaction between rifampicin and moxifloxacin should be investigated. PATIENTS AND METHODS Nineteen Indonesian patients with pulmonary TB who were in the last month of their TB treatment completed a 1-arm, 2-period, fixed-order pharmacokinetic study. In phase 1 of the study, they received 400 mg of moxifloxacin every day for 5 days in addition to 450 mg of rifampicin and 600 mg of isoniazid 3 times per week. In phase 2 of the study, after a 1-month washout period, patients received moxifloxacin for another 5 days (without rifampicin and isoniazid). A 24-h pharmacokinetic curve for moxifloxacin was recorded on the last day of both study periods, and its pharmacokinetic parameters were evaluated for an interaction with rifampicin, using a bioequivalence approach. RESULTS Coadministration of moxifloxacin with rifampicin and isoniazid resulted in an almost uniform decrease in moxifloxacin exposure (in 18 of 19 patients). The geometric means for the ratio of phase 1 area under the curve to phase 2 area under the curve and for the ratio of phase 1 peak plasma concentration to phase 2 peak plasma concentration were 0.69 (90% confidence interval, 0.65-0.74) and 0.68 (90% confidence interval, 0.64-0.73), respectively. The median time to reach peak plasma concentration for moxifloxacin was prolonged from 1 h to 2.5 h when combined with rifampicin and isoniazid (P=.003). CONCLUSIONS Coadministration of moxifloxacin with intermittently administered rifampicin and isoniazid results in reduced moxifloxacin plasma concentrations, which is most likely the result of induced glucuronidation or sulphation by rifampicin. Further studies are warranted to evaluate the impact of the interaction on the outcome of TB treatment.

Pharmacokinetics and Tolerability of a Higher Rifampin Dose versus the Standard Dose in Pulmonary Tuberculosis Patients

ABSTRACT Rifampin is a key drug for tuberculosis (TB) treatment. The available data suggest that the currently applied 10-mg/kg of body weight dose of rifampin may be too low and that increasing the dose may shorten the treatment duration. A double-blind randomized phase II clinical trial was performed to investigate the effect of a higher dose of rifampin in terms of pharmacokinetics and tolerability. Fifty newly diagnosed adult Indonesian TB patients were randomized to receive a standard (450-mg, i.e., 10-mg/kg in Indonesian patients) or higher (600-mg) dose of rifampin in addition to other TB drugs. A full pharmacokinetic curve for rifampin, pyrazinamide, and ethambutol was recorded after 6 weeks of daily TB treatment. Tolerability was assessed during the 6-month treatment period. The geometric means of exposure to rifampin (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were increased by 65% (P < 0.001) in the higher-dose group (79.7 mg·h/liter) compared to the standard-dose group (48.5 mg·h/liter). Maximum rifampin concentrations (Cmax) were 15.6 mg/liter versus 10.5 mg/liter (49% increase; P < 0.001). The percentage of patients for whom the rifampin Cmax was ≥8 mg/liter was 96% versus 79% (P = 0.094). The pharmacokinetics of pyrazinamide and ethambutol were similar in both groups. Mild (grade 1 or 2) hepatotoxicity was more common in the higher-dose group (46 versus 20%; P = 0.054), but no patient developed severe hepatotoxicity. Increasing the rifampin dose was associated with a more than dose-proportional increase in the mean AUC0-24 and Cmax of rifampin without affecting the incidence of serious adverse effects. Follow-up studies are warranted to assess whether high-dose rifampin may enable shortening of TB treatment.

Implications of the global increase of diabetes for tuberculosis control and patient care

Objectives  To review the current knowledge about tuberculosis (TB) and diabetes, assessing the implication of the global increase of diabetes for TB control and patient care.

Pharmacokinetics of Antituberculosis Drugs in Pulmonary Tuberculosis Patients with Type 2 Diabetes

ABSTRACT Altered pharmacokinetics of antituberculosis drugs may contribute to an increased risk of tuberculosis treatment failure for diabetic patients. We previously found that rifampin exposure was 2-fold lower in diabetic than in nondiabetic tuberculosis patients during the continuation phase of treatment. We now examined the influence of diabetes on the pharmacokinetics of antituberculosis drugs in the intensive phase of tuberculosis treatment, and we evaluated the effect of glycemic control. For this purpose, 18 diabetic and 18 gender- and body weight-matched nondiabetic tuberculosis patients were included in an Indonesian setting. Intensive pharmacokinetic sampling was performed for rifampin, pyrazinamide, and ethambutol at steady state. The bioavailability of rifampin was determined by comparing rifampin exposure after oral versus intravenous administration. Pharmacokinetic assessments were repeated for 10 diabetic tuberculosis patients after glycemic control. No differences in the areas under the concentration-time curves of the drugs in plasma from 0 to 24 h postdose (AUC0-24), the maximum concentrations of the drugs in plasma (Cmax), the times to Cmax (Tmax), and the half-lives of rifampin, pyrazinamide, and ethambutol were found between diabetic and nondiabetic tuberculosis patients in the intensive phase of tuberculosis treatment. For rifampin, oral bioavailability and metabolism were similar in diabetic and nondiabetic patients. The pharmacokinetic parameters of antituberculosis drugs were not correlated with blood glucose levels or glucose control. We conclude that diabetes does not alter the pharmacokinetics of antituberculosis drugs during the intensive phase of tuberculosis treatment. The reduced exposure to rifampin of diabetic patients in the continuation phase may be due to increased body weight and possible differences in hepatic induction. Further research is needed to determine the cause of increased tuberculosis treatment failure among diabetic patients.

Clinical management of concurrent diabetes and tuberculosis and the implications for patient services

Diabetes triples the risk for active tuberculosis, thus the increasing burden of type 2 diabetes will help to sustain the present tuberculosis epidemic. Recommendations have been made for bidirectional screening, but evidence is scarce about the performance of specific tuberculosis tests in individuals with diabetes, specific diabetes tests in patients with tuberculosis, and screening and preventive therapy for latent tuberculosis infections in individuals with diabetes. Clinical management of patients with both diseases can be difficult. Tuberculosis patients with diabetes have a lower concentration of tuberculosis drugs and a higher risk of drug toxicity than tuberculosis patients without diabetes. Good glycaemic control, which reduces long-term diabetes complications and could also improve tuberculosis treatment outcomes, is hampered by chronic inflammation, drug-drug interactions, suboptimum adherence to drug treatments, and other factors. Besides drug treatments for tuberculosis and diabetes, other interventions, such as education, intensive monitoring, and lifestyle interventions, might be needed, especially for patients with newly diagnosed diabetes or those who need insulin. From a health systems point of view, delivery of optimum care and integration of services for tuberculosis and diabetes is a huge challenge in many countries. Experience from the combined tuberculosis and HIV/AIDS epidemic could serve as an example, but more studies are needed that include economic assessments of recommended screening and systems to manage concurrent tuberculosis and diabetes.

Isoniazid, Rifampin, and Pyrazinamide Plasma Concentrations in Relation to Treatment Response in Indonesian Pulmonary Tuberculosis Patients

ABSTRACT Numerous studies have reported low concentrations of antituberculosis drugs in tuberculosis (TB) patients, but few studies have examined whether low drug concentrations affect TB treatment response. We examined steady-state plasma concentrations of isoniazid, rifampin, and pyrazinamide at 2 h after the administration of drugs (C2 h) among 181 patients with pulmonary tuberculosis in Indonesia and related these to bacteriological response during treatment. C2 h values below reference values for either isoniazid, rifampin, or pyrazinamide were found in 91% of patients; 60% had at least two low C2 h concentrations. The isoniazid C2 h was noticeably lower in fast versus slow acetylators (0.9 mg/liter versus 2.2 mg/liter, P < 0.001). At the end of treatment, 82% of the patients were cured, whereas 30 patients (17%) had dropped out during the study, and 2 patients (1%) failed treatment. No association was found between C2 h concentrations and sputum culture results at 8 weeks of treatment. Post hoc analysis showed that patients with low pyrazinamide C2 h (P = 0.01) and patients with large extensive lung lesions (P = 0.01) were at risk of at least one positive culture at week 4, 8, or 24/32. Antituberculosis drug concentrations were often low, but treatment response was nevertheless good. No association was found between drug concentrations and 8 weeks culture conversion, but low pyrazinamide drug concentrations may be associated with a less favorable bacteriological response. The use of higher doses of pyrazinamide may warrant further investigation.

Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis

Recent data suggest that intensified antimicrobial treatment may improve the outcome of tuberculous meningitis (TBM). Considering that drug exposure is the intermediate link between dose and effect, we examined the concentration-response relationship for rifampicin and moxifloxacin in TBM patients. In an open-label, phase 2 clinical trial performed in Indonesia (ClinicalTrials.gov NCT01158755), 60 TBM patients were randomised to receive standard-dose (450mg oral) or high-dose rifampicin (600mg intravenous) plus either oral moxifloxacin (400mg or 800mg) or ethambutol (750mg). After 14 days, all patients continued with standard tuberculosis treatment. Pharmacokinetic sampling was performed once in every patient during the first three critical days. Differences in exposure between patients who died or survived were tested with independent samples t-tests. The relationship between drug exposure and mortality was examined using Cox regression. Compared with patients who died during the 2 weeks of intensified treatment, surviving patients had significantly higher rifampicin plasma AUC0-6h, plasma Cmax and CSF Chighest. Additionally, patients had a 32-43% lower relative likelihood of dying with an interquartile range increase in rifampicin exposure. Moxifloxacin exposure did not show a clear relationship with survival. From exposure-response curves, a rifampicin plasma AUC0-6h of ∼70mg·h/L (AUC0-24h of ∼116mgh/L) and a Cmax of ∼22mg/L were deduced as minimum target values for treatment. A strong concentration-effect relationship was found, with higher rifampicin exposure leading to better TBM survival. The current treatment dose of rifampicin is suboptimal; higher doses of rifampicin should be evaluated.

Evaluation of High- versus Standard-Dose Rifampin in Indonesian Patients with Pulmonary Tuberculosis

We previously found peak plasma concentrations of rifampin below 4 mg/liter in 70% of Indonesian tuberculosis (TB) patients treated with 10 mg rifampin/kg of body weight daily (6), much below the reference concentration of ≥8 mg/liter (5). In addition, both murine models (1) and studies with TB patients (3) suggest that the typical 10-mg/kg dose of rifampin may be too low and that a higher dose may reduce treatment duration (4). Indeed, a regimen incorporating a higher dose of 1,200 mg rifampin daily yielded much faster conversion of sputum culture (2). Based on these findings, we decided to investigate the effect of increasing the dose of rifampin in terms of pharmacokinetics and tolerability. In an open-label phase II randomized clinical trial in an urban clinic in Indonesia, consecutive patients with microbiologically proven pulmonary TB were randomized to a standard (450 mg; 10 mg/kg) or high (600 mg) dose of rifampin. High and standard doses of rifampin were administered every day in the intensive phase and three times weekly in the continuation phase of treatment. All other TB drugs were dosed according to the protocols of the Indonesian National TB Program. All patients provided written informed consent, and the study was approved by the local institutional review board. After 4 and 8 weeks of treatment, blood samples were collected at the time of peak plasma concentration of rifampin, 2 hours (5) after the witnessed intake of TB drugs on an empty stomach. Plasma was separated immediately and stored at −80°C until measurement of rifampin concentrations with a validated high-performance liquid chromatographic assay. Patients were questioned actively for possible adverse events, and liver transaminases were monitored. The simultaneous effects of the dose of rifampin and the week of treatment on the rifampin peak plasma concentrations were evaluated with a two-way mixed analysis of variance. Fifty patients were included, and 46 completed the study (54% male; median age, 25 years; range, 18 to 50 years). Patients from both groups had similar body weights, and the median dose of rifampin corresponded to 13.3 mg/kg in the 600-mg-dose group and 10.3 mg/kg in the 450-mg-dose group. The mean peak plasma concentration of rifampin was higher in the 600-mg-dose group (11.1 versus 8.0 mg/liter; F = 8.77; P = 0.005). Mean plasma concentrations were similar in weeks 4 and 8. In week 4, the percentages of patients with rifampin peak plasma concentrations of ≥8 mg/liter were 48% (for the 450-mg dose) and 78% (for the 600-mg dose) (χ2; P = 0.03) (Fig. ​(Fig.1).1). One patient receiving 600 mg developed a reversible elevation of the liver transaminase level to >5 times normal, while four patients (two in each study arm) showed mildly elevated transaminase levels. No differences were noted in terms of tolerability. FIG. 1. Two-hour plasma rifampin concentrations after 4 weeks of TB treatment in Indonesian patients randomized to standard-dose (450 mg) or high-dose (600 mg) rifampin daily. Rifampin doses were combined with standard-dose isoniazid, pyrazinamide, and ethambutol. ... In conclusion, this trial in Indonesia shows that a higher dose of rifampin significantly increases the proportion of patients with rifampin peak plasma concentrations above the reference value of 8 mg/liter. Blinded studies with more-extensive pharmacokinetic assessments will provide more insight into the merits of high-dose rifampin and may pave the road for studies evaluating high-dose rifampin in shorter treatment regimens.