Decreased Dolutegravir and Efavirenz Concentrations With Preserved Virological Suppression in Patients With Tuberculosis and Human Immunodeficiency Virus Receiving High-Dose Rifampicin.

BACKGROUND: Higher doses of rifampicin may improve treatment outcomes and reduce the duration of tuberculosis (TB) therapy. However, drug-drug interactions with antiretroviral therapy (ART) and safety in people with human immunodeficiency virus (HIV) have not been evaluated. METHODS: This was a randomized, open-label trial where newly diagnosed TB patients were randomized to higher (35 mg/kg) or standard (10 mg/kg) daily-dose rifampicin. ART treatment-naive patients were randomized to dolutegravir- or efavirenz-based ART. At week 6, trough dolutegravir or mid-dose efavirenz plasma concentrations were assayed. HIV viral load was measured at week 24. RESULTS: Among 128 patients randomized, the median CD4 count was 191 cells/mm3. The geometric mean ratio (GMR) for trough dolutegravir concentrations on higher- vs standard-dose rifampicin was 0.57 (95% confidence interval [CI], .34-.97; P = .039) and the GMR for mid-dose efavirenz was 0.63 (95% CI, .38-1.07; P = .083). There was no significant difference in attainment of targets for dolutegravir trough or efavirenz mid-dose concentrations between rifampicin doses. The incidence of HIV treatment failure at week 24 was similar between rifampicin doses (14.9% vs 14.0%, P = .901), as was the incidence of drug-related grade 3-4 adverse events (9.8% vs 6%). At week 8, fewer patients remained sputum culture positive on higher-dose rifampicin (18.6% vs 37.0%, P = .063). CONCLUSIONS: Compared with standard-dose rifampicin, high-dose rifampicin reduced dolutegravir and efavirenz exposures, but HIV suppression was similar across treatment arms. Higher-dose rifampicin was well tolerated among people with HIV and associated with a trend toward faster sputum culture conversion. CLINICAL TRIALS REGISTRATION: NCT03982277.

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis.

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial.

BACKGROUND: Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. METHODS: TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). RESULTS: Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). CONCLUSIONS: In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. CLINICAL TRIALS REGISTRATION: NCT02958709.

High-dose rifampicin for 3 months after culture conversion for drug-susceptible pulmonary tuberculosis.

BACKGROUND: This study aimed to determine whether a shorter high-dose rifampicin regimen is non-inferior to the standard 6-month tuberculosis regimen. METHOD: This multicenter, randomized, open-label, non-inferiority trial enrolled participants with respiratory specimen positivity by Xpert MTB/RIF assay or Mycobacterium tuberculosis culture without rifampicin-resistance. Participants were randomized at 1:1 to the investigational or control group. The investigational group received high-dose rifampicin (30 mg/kg/day), isoniazid, and pyrazinamide until culture conversion, followed by high-dose rifampicin and isoniazid for 12 weeks. The control group received the standard 6-month regimen. The primary outcome was the rate of unfavorable outcomes at 18 months post-randomization. The non-inferiority margin was set at <6% difference in unfavorable outcomes rates. RESULTS: Between 4 November 2020 and 3 January 2022, 76 participants were enrolled. Of these, 58 were included in the modified intention-to-treat analysis. Unfavorable outcomes occurred in 10 (31.3%) of 32 in the control group and 10 (38.5%) of 26 in the investigational group. The difference was 7.2% (95% confidence interval, ∞ to 31.9%), failing to prove non-inferiority. Serious adverse events and grade 3 or higher adverse events did not differ between the groups. CONCLUSIONS: The shorter high-dose rifampicin regimen failed to demonstrate non-inferiority but had an acceptable safety profile. Trial registration ClinicalTrials.gov NCT04485156.

Comparative evaluation of intensified short course regimen and standard regimen for adults TB meningitis: a protocol for an open label, multi-center, parallel arms, randomized controlled superiority trial (INSHORT trial).

BACKGROUND: Despite several incremental improvements in the management of tuberculous meningitis (TBM), the mortality rates remain high. In spite of national and international guidelines, variation in the choice, dose, and duration of drugs exist between countries and clinicians. We propose to evaluate a shorter and more effective regimen containing agents with augmented intracerebral drug exposure and anti-inflammatory approaches to improve disability-free survival among patients with TBM. Our strategy incorporates the various developments in the field of TBM over the last two decades and only few trials have evaluated a composite of these strategies in the overall outcomes of TBM. METHODS: An open label, parallel arms, randomized controlled superiority trial will be conducted among 372 participants across 6 sites in India. Eligible participants will be randomly allocated in 1:1:1 ratio into one of the three arms. The intervention arm consists of 2 months of high-dose rifampicin (25 mg/kg), moxifloxacin (400 mg), pyrazinamide, isoniazid, aspirin (150 mg), and steroids followed by rifampicin, isoniazid, and pyrazinamide for 4 months. The second intervention arm includes all the drugs as per the first arm except aspirin and the patients in the control arm will receive treatment according to the National TB Elimination Program guidelines. All participants will be followed up for 1 year after the treatment.  DISCUSSION: Current WHO regimens have agents with poor central nervous system drug exposure and is too long. It does not reflect the accumulating evidence in the field. We propose a comprehensive clinical trial incorporating the emerging evidence accrued over the last two decades to shorten the duration and improve the treatment outcomes. This multi-centric trial may generate crucial evidence with policy and practice implications in the treatment of TBM. TRIAL REGISTRATION: Clinical Trial Registry India CTRI/2023/05/053314. Registered on 31 May 2023 ( https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=ODYzMzg=&Enc=&userName=CTRI/2023/05/053314 ). CLINICALTRIALS: gov NCT05917340. Registered on 6 August 2023 ( https://classic. CLINICALTRIALS: gov/ct2/show/NCT05917340 ). PROTOCOL VERSION: Version 1.3 dated 12 July 2023.

Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial.

BACKGROUND: HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. METHODS: This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. DISCUSSION: Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986.

The quest to deliver high-dose rifampicin: can the inhaled approach help?

INTRODUCTION: Tuberculosis (TB) is a global health problem that poses a challenge to global treatment programs. Rifampicin is a potent and highly effective drug for TB treatment; however, higher oral doses than the standard dose (10 mg/kg/day) rifampicin may offer better efficacy in TB treatment. AREAS COVERED: High oral dose rifampicin is not implemented in anti-TB regimens yet and requires about a 3-fold increase in dose for increased efficacy. We discuss inhaled delivery of rifampicin as an alternative or adjunct to oral high-dose rifampicin. Clinical results of safety, tolerability, and patient compliance with antibiotic dry powder inhalers are reviewed. EXPERT OPINION: Clinical trials suggest that an approximately 3-fold increase in the standard oral dose of rifampicin may be required for better clinical outcomes. On the other hand, animal studies suggest that inhaled rifampicin can deliver a high concentration of the drug to the lungs and achieve approximately double the plasma concentration than that from oral rifampicin. Clinical trials on inhaled antibiotics suggest that dry powder inhalation is a patient-friendly and well-tolerated approach in treating respiratory infections compared to conventional treatments. Rifampicin, a well-known anti-TB drug given orally, is a good candidate for clinical development as a dry powder inhaler.

Phenotypically occult multidrug-resistant Mycobacterium tuberculosis: dilemmas in diagnosis and treatment.

OBJECTIVES: The clinical significance of the emergence of Mycobacterium tuberculosis (MTB) isolates that contain rpoB mutations (genotypic resistance), but are phenotypically susceptible to rifampicin (RIF G(R) P(S)), remains uncertain. The aim of this study was to determine the prevalence of MTB cases that demonstrate this discordant rifampicin resistance pattern and to establish whether these patients have poorer treatment outcomes with rifampicin-based regimens. METHODS: rpoB sequencing was performed on all MTB isolates demonstrating phenotypic resistance to one or more first-line antituberculosis agents (excluding rifampicin). Rifampicin MICs were determined for rpoB mutation-positive isolates and clinical case notes were reviewed to identify treatment outcomes in these patients. RESULTS: Of the 214 phenotypically drug (excluding rifampicin)-resistant isolates tested, 5 contained rpoB mutations (4 isoniazid resistant and 1 pyrazinamide resistant). These isolates demonstrated elevated rifampicin MICs (low-level resistance), despite testing susceptible using phenotypic broth-based methods. One patient experienced a relapse of tuberculosis (TB) 2 years after completion of a rifampicin-containing regimen. These findings are consistent with a recent study that reported treatment failure with rifampicin-based regimens in patients with isoniazid-resistant MTB and genotypic rifampicin resistance. CONCLUSIONS: While MTB RIF G(R) P(S) strains remain relatively uncommon, they can be associated with low-level rifampicin resistance and poorer treatment outcomes with rifampicin-based regimens. This recently recognized form of multidrug-resistant TB should be adequately detected and managed.

The impact of enteral feeding and therapeutic monitoring of rifampicin with dose escalation in critically ill patients with tuberculosis.

OBJECTIVES: Critically ill patients with tuberculosis (TB) face a high mortality risk and require effective treatment. There is a paucity of data on rifampicin pharmacokinetics, the impact of continuous enteral feeding on drug absorption, and the potential of therapeutic drug monitoring (TDM) to optimize drug exposure in these patients. METHODS: We performed a sequential pharmacokinetic study to determine the impact of feeding and TDM with rifampicin dose escalation in critically ill patients with TB. Noncompartmental pharmacokinetic analysis was performed. RESULTS: Among 20 critically ill patients (40% were HIV-infected), median rifampicin Cmax (maximum serum concentration) in the fasted and fed states were 5.1 µg/ml versus 3.3 µg/ml, respectively (P <0.0001; geometric mean ratio 1.95; 90% confidence interval 1.46-2.60). The proportion of patients with low rifampicin concentrations in the fasted and fed states was 80% vs 100% (P-value = 0.1336). Optimized dosing led to a per-patient median rifampicin dosing of 24.6 mg/kg and a median Cmax increase from 2.4 µg/ml to 17.8 µg/ml (P-value = 0.0005; geometric mean ratio 8.29; 90% confidence interval 3.88-17.74). TDM-guided dose escalation increased the proportion of patients achieving the suggested target rifampicin concentration compared with standard dosing (83% vs 0%, P-value = 0.004). CONCLUSION: We found low rifampicin concentrations in all patients receiving continuous enteral feeding. TDM-guided dose escalation provided an effective strategy to achieve target drug exposure in these critically ill patients with TB.

Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): study protocol for a phase III randomized controlled trial.

BACKGROUND: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB), particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40% in HIV-negative patients and up to 70% in HIV-co-infected patients. To reduce TBM-induced morbidity and mortality, the INTENSE-TBM trial evaluates two interventions in both HIV-infected and uninfected patients: an anti-TB treatment intensification using oral high-dose rifampicin (35 mg/kg daily) and linezolid (1200 mg daily and then 600 mg daily) during the first 8 weeks of the anti-TB treatment and the use of adjunctive aspirin (200 mg daily). METHODS: This is a randomized controlled, phase III, multicenter, 2 × 2 factorial plan superiority trial. The trial has four arms, combining the two experimental treatments (intensified TBM regimen and aspirin) with the two reference treatments (WHO standard TB treatment and placebo), and is open-label for anti-TB treatment and double-blind placebo-controlled for aspirin treatment. This trial is conducted in adults or adolescents of age ≥15 years with TBM defined as "definite," "probable," or "possible" using Tuberculosis Meningitis International Research Consortium criteria, in four African countries: Ivory Coast, Madagascar, Uganda, and South Africa. The primary outcome is all-cause death between inclusion and week 40. DISCUSSION: The INTENSE-TBM trial represents a key opportunity to enhance TBM treatment with widely available existing drugs notably in high-incidence settings of both TB and HIV. The trial design is pragmatic and the results will permit early and effective applications in TBM patient care, in both HIV and TB high-incidence countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT04145258. Registered on October 30, 2019.

High-Dose Rifampicin Mediated Systemic Alterations of Cytokines, Chemokines, Growth Factors, Microbial Translocation Markers, and Acute-Phase Proteins in Pulmonary Tuberculosis.

High-dose rifampicin (HDR) is now undergoing clinical trials to improve the efficacy of anti-tuberculosis treatment (ATT). However, the influence of HDR in the modulation of different cytokines, chemokines/growth factors, microbial translocation markers (MTMs), and acute-phase proteins (APPs) in pulmonary tuberculosis (PTB) is not well known. PTB individuals were separated into three different arms (R10, R25, and R35) based on their rifampicin dosage. We examined the circulating levels of Type 1, Type 2, pro-inflammatory/regulatory cytokines, chemokines/growth factors, MTMs, and APPs at baseline and after completion of the second month of ATT by ELISA. The baseline levels of cytokines, chemokines/growth factors, MTMs, and APPs did not (except IL-5, IL-6, IL-17A, MCP-1, MIP-1ß, GCSF, SAA, ⍺2 MG, Hp) significantly differ between the study individuals. However, at the second month, the plasma levels of Type 1 (TNFα and IFNγ), Type 2 (IL-4, IL-5, and IL-13), pro-inflammatory/regulatory cytokines (IL-6, IL-17A, IL-10, and GMCSF), and APPs were significantly decreased in R35 regimen- compared to R25 and/or R10 regimen-treated PTB individuals. In contrast, the plasma levels of IL-2, IL-8, MCP-1, MIP-1ß, GSF, and MTMs were significantly increased in the R35 regimen compared to R25 and/or R10 regimen-treated PTB individuals. Overall, our data reveal that HDR could potentially be beneficial for host immunity by altering different immune and inflammatory markers.

Buruli-RifDACC: Evaluation of the efficacy and cost-effectiveness of high-dose versus standard-dose rifampicin on outcomes in Mycobacteriumulcerans disease, a protocol for a randomised controlled trial in Ghana.

Background: Buruli ulcer (BU) can lead to disfiguring ulcers and permanent disability. The 2030 World Health Organization (WHO) road map for Neglected Tropical Diseases (NTDs) calls for major scaling up in diagnosis and management to eliminate disability due to the disease. Current treatment for BU is with daily oral rifampicin (10mg/kg dose) and clarithromycin (15mg/kg dose) for eight weeks, combined with standard gauze wound dressings. Dialkylcarbamoyl chloride (DACC)-coated dressings have been shown to irreversibly bind bacteria on wound surfaces resulting in their removal when dressings are changed. This trial aims to determine whether combining a high-dose oral rifampicin regimen with DACC dressings can improve the rate of wound healing relative to standard-dose oral rifampicin combined with DACC dressings. Methods: This is an individual, multi-centre Phase 3 randomised controlled trial, which will be conducted in three clinical sites in Ghana. The primary outcome measure will be the mean time to clearance of viable mycobacteria. Cost and health-related quality of life data will be collected, and a cost-effectiveness analysis will be performed. Discussion: The findings from this trial could lead to a change in how BU is treated. A shorter but more efficacious regimen would lead to improved treatment outcomes and potentially substantial financial and economic savings. Trial registration: Pan African Clinical Trials Repository (registration number; PACTR202011867644311). Registered on 30 th November 2020.

Buruli ulcer (BU), caused by Mycobacterium ulcerans, manifests clinically as a wound or swelling. There are several approaches for managing this condition. One is the availability of two antibiotics, usually rifampicin in combination with clarithromycin, that can be used to treat the disease. Rifampicin is thought to be the most important of these two drugs. Scientists have found out that a higher dose of rifampicin is safe and may help improve healing outcome and shorten the duration of treatment. Individuals with BU wounds also go through wound dressing procedures at their hospitals and health centres. Commonly, wounds are dressed using Vaseline gauze and bandages. However, it has been observed that some affected individuals heal faster than others even with the antibiotic treatment. Some still have living organisms in their wounds many weeks after the antibiotic treatment. There is a new dressing material called DACC which is believed to permanently bind bacteria on the wound surface leading to their removal when the dressings are changed. This may be a good way to treat and prevent infection without the use of more drugs. This study aims to determine whether combining a high-dose oral rifampicin regimen with DACC dressings can improve the rate of wound healing relative to standard-dose oral rifampicin combined with DACC dressings. Furthermore, cost and health-related quality of life data will be collected and a cost-effectiveness analysis will be performed. The findings from this trial could lead to a change in how BU is treated. A shorter but more efficacious regimen would lead to improved treatment outcomes and potentially substantial financial and economic savings.

Safety and efficacy of high-dose rifampicin in the management of tuberculosis meningitis: Systematic review and meta-analysis.

Background: Mycobacterium tuberculosis (TB) practically affects any part of the body, but when the brain is involved, the consequences are devastating. Tuberculous meningitis (TBM) is the most severe form of drug-susceptible TB, with an estimation of more than 100,000 new cases occurring every year and a high mortality rate globally. The treatment strategy is based on pulmonary TB (PTB) management regimens which consider rifampicin as the backbone. Optimal treatment regimens for PTB may not be the most effective option for TBM due to difference in TB drug penetration across the blood-cerebrospinal fluid barrier, hence the need for other treatment options. This study aims to review the efficacy and safety of higher doses of rifampicin (>10 mg/kg) compared to 10 mg/kg rifampicin as part of standard therapy for the treatment of TBM. Methods: A systematic review and meta-analysis was conducted to assess the efficacy and safety of high-dose rifampicin for TBM. A search was done on PubMed, Google Scholar, and Cochrane library databases without publication date limit to identify studies providing data on the use of high-dose rifampicin for the treatment of TBM. Titles and abstracts were screened for relevance by three reviewers. Two reviewers used a predefined checklist on the inclusion criteria to assess full text for their eligibility in the review. A heterogeneity test was conducted to assess the variations among study outcomes. The risk ratio (RR) with a 95% confidence interval (CI) was calculated as a measure of intervention effect. The study is registered on PROSPERO and the registration number is CRD42020212737. Results: Five Phase 2 trials with a total of 1028 participants were included in this meta-analysis. All the five trials were used to analyze safety data, which found that there was no significant increase in the risk of Grade 3-5 adverse events in high-dose rifampicin (RR = 1.05; 95% CI = 0.95-1.18). Only four of them were included for the analysis of efficacy. The findings indicated that exposure to high-dose rifampicin is not associated with a reduced risk of mortality (RR = 0.95; 95% CI = 0.78-1.16). Conclusions: It can be concluded from this meta-analysis that there is no significant relation of high-dose rifampicin with adverse events and the reduction of mortality in TBM patients. Whether in future optimized TBM treatment regimen will include high-dose rifampicin or not should be determined by a large-scale clinical trial.

Pharmacokinetics and pharmacogenetics of anti-tubercular drugs: a tool for treatment optimization?

INTRODUCTION: WHO global strategy is to end tuberculosis epidemic by 2035. Pharmacokinetic and pharmacogenetic studies are increasingly performed and might confirm their potential role in optimizing treatment outcome in specific settings and populations. Insufficient drug exposure seems to be a relevant factor in tuberculosis outcome and for the risk of phenotypic resistance. Areas covered: This review discusses available pharmacokinetic and pharmacogenetic data of first and second-line antitubercular agents in relation to efficacy and toxicity. Pharmacodynamic implications of optimized drugs and new options regimens are reviewed. Moreover a specific session describes innovative investigations on drug penetration. Expert opinion: The optimal use of available antitubercular drugs is paramount for tuberculosis control and eradication. Whilst trials are still on-going, higher rifampicin doses should be reserved to treatment for tubercular meningitis. Therapeutic Drug Monitoring with limiting sampling strategies is advised in patients at risk of failure or with slow treatment response. Further studies are needed in order to provide definitive recommendations of pharmacogenetic-based individualization: however lower isoniazid doses in NAT2 slow acetylators and higher rifampicin doses in individuals with SLCO1B1 loss of function genes are promising strategies. Finally in order to inform tailored strategies we need more data on tissue drug penetration and pharmacological modelling.

Considerations in preparing for clinical studies of inhaled rifampicin to enhance tuberculosis treatment.

Drug delivery via the inhaled route has advantages for treating local and systemic diseases. Pulmonary drug delivery may have potential in treating tuberculosis (TB), which is mainly localised in the lung (pulmonary tuberculosis ∼75%) while also affecting other organs (extra-pulmonary tuberculosis). Currently, rifampicin, a first-line anti-tubercular drug, is given orally and the maximum daily oral dose is the lesser of 10 mg/kg or 600 mg. Since only a small fraction of this dose is available in the lung, concentrations may frequently fail to reach bactericidal levels, and therefore, contribute to the development of multi-drug resistant pulmonary TB. Pulmonary delivery of rifampicin, either alone or in addition to the standard oral dose, has the potential to achieve a high concentration of rifampicin in the lung at a relatively low administered dose that is sufficient to kill bacteria and reduce the development of drug resistance. As yet, no clinical study in humans has reported the pharmacokinetics or the efficacy of pulmonary delivery of rifampicin for TB. This review discusses the opportunities and challenges of rifampicin delivery via the inhaled route and important considerations for future clinical studies on high dose inhaled rifampicin are illustrated.

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.