Wiel C. M. de Lange

Antituberculosis drug‐induced hepatotoxicity: Concise up‐to‐date review

The cornerstone of tuberculosis management is a 6‐month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug‐induced hepatotoxicity, discuss the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and describe risk factors and management of antituberculosis drug‐induced hepatotoxicity. The reported incidence of antituberculosis drug‐induced hepatotoxicity, the most serious and potentially fatal adverse reaction, varies between 2% and 28%. Risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre‐existent liver disease. Still, it is difficult to predict what patient will develop hepatotoxicity during tuberculosis treatment. The exact mechanism of antituberculosis drug‐induced hepatotoxicity is unknown, but toxic metabolites are suggested to play a crucial role in the development, at least in the case of isoniazid. Priorities for future studies include basic studies to elucidate the mechanism of antituberculosis drug‐induced hepatotoxicity, genetic risk factor studies and the development of shorter and safer tuberculosis drug regimens.

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking. TBNET consensus statement on the management of patients with MDR/XDR-TB has been released in the Eur Respir J http://ow.ly/uizRD

Clinical Relevance of Mycobacterium szulgai in The Netherlands

BACKGROUND The clinical relevance of Mycobacterium szulgai isolates is unknown, and available literature focuses on case reports of M. szulgai disease. We assessed the clinical relevance of M. szulgai isolated from patients in The Netherlands. METHODS We reviewed medical files for all 21 patients in The Netherlands from whom M. szulgai was isolated during 1999-2006, applying the diagnostic criteria of the American Thoracic Society for nontuberculous mycobacterial infection. Random amplified polymorphic DNA genotyping was performed using IS986, OPA-2, and OPA-18 as primers. RESULTS Of the 21 patients, 16 (76%) met the American Thoracic Society diagnostic criteria and were thus likely to have M. szulgai disease. Pulmonary M. szulgai disease was the most common presentation, with extrapulmonary disease restricted to patients with an impaired systemic immunity. Although treatment regimens varied in content and duration, the outcomes were mostly favorable. Both overtreatment and undertreatment were noticed. Random amplified polymorphic DNA genotyping revealed a higher degree of interpatient variability, with limited intrapatient variability, suggesting persisting monoclonal infection and good reproducibility. No genotype was associated with clinical relevance. CONCLUSIONS Clinical isolation of M. szulgai generally represents true disease and demands careful follow-up. Extrapulmonary disease occurs in patients with impaired immunity. Adherence to diagnostic guidelines can be improved.

Mycobacterium xenopi clinical relevance and determinants, the Netherlands.

Clinical isolation of M. xenopi represents true infection in 51% of cases; genotype is a major determinant.

Pulmonary Mycobacterium szulgai infection and treatment in a patient receiving anti-tumor necrosis factor therapy

Background A 54-year-old man with a 22-year history of rheumatoid arthritis and an 8-year history of chronic obstructive pulmonary disease presented with dyspnea on exertion, nonproductive cough and fatigue of 1 months duration. His medication at presentation consisted of etanercept, azathioprine, naproxen and inhaled fluticasone and salbutamol.Investigations At presentation, the patient underwent physical examination, chest X-ray and high-resolution CT, blood tests, and bronchoalveolar lavage fluid analysis including auramine stains and gene sequence analysis of cultured Mycobacterium szulgai. The patient underwent minithoracotomy after 6 months, and bronchoalveolar lavage fluid analysis, culture and chest X-ray after 18 months. Further chest imaging and culture of sputum samples were performed another year later.Diagnosis Pulmonary M. szulgai infection.Management Triple drug therapy with rifampicin, ethambutol hydrochloride and clarithromycin. Anti-tumor necrosis factor treatment was continued.

Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis.

Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of already available drugs. Six drugs with antimicrobial activity (phenothiazine, metronidazole, doxycycline, disulfiram, tigecycline and co-trimoxazole) are not listed in the World Health Organization guidelines on MDR-TB treatment but could be potential candidates for evaluation against Mycobacterium tuberculosis. A systematic review was conducted to evaluate antituberculous activity of these drugs against M. tuberculosis. We searched PubMed, Google Scholar and Embase for English articles published up to December 31, 2012. We reviewed in vitro, in vivo and clinical antituberculous activity of these drugs in addition to pharmacokinetics and side-effects. Of the drugs effective against actively replicating M. tuberculosis, co-trimoxazole seems to be the most promising, because of its consistent pharmacokinetic profile, easy penetration into tissue and safety profile. For the dormant state of TB, thioridazine may play a potential role as an adjuvant for treatment of MDR-TB. A strategy consisting of pharmacokinetic/pharmacodynamic studies, dose finding and phase III studies is needed to explore the role of these drugs in MDR-TB treatment. Six antimicrobial drugs are not listed in WHO guidelines on MDR-TB treatment but could offer potential for TB treatment http://ow.ly/q0HRV

Evaluation of co-trimoxazole in the treatment of multidrug-resistant tuberculosis

Co-trimoxazole (SXT), a combination of sulfamethoxazole and trimethoprim, has shown in vitro activity against Mycobacterium tuberculosis. However, the pharmacokinetic and pharmacodynamic parameters of SXT in multidrug-resistant (MDR) tuberculosis (TB) are, thus far, lacking. Therefore, we evaluated its pharmacokinetics and drug susceptibility, along with its tolerability during treatment. Based on drug susceptibility testing, MDR-TB patients received SXT as a part of their MDR treatment. The pharmacokinetic parameters of sulfamethoxazole, the effective component of SXT against M. tuberculosis, were evaluated. The ratio of the area under the curve from 0 to 24 h (AUC0–24) to minimum inhibitory concentration (MIC) was used as the best pharmacokinetic/pharmacodynamic parameter to predict the efficacy of sulfamethoxazole. Adverse effects of SXT were also evaluated. 10 patients with MDR-TB (one of whom had extensively drug-resistant TB) received 480 mg of SXT with a median dosage of 6.5 mg·kg−1 of SXT (range 6.1–6.8 mg·kg−1) once daily for a median treatment period of 381 days (range 129–465 days). In two patients, the dose was escalated to 960 mg. The free AUC0–24/MIC of sulfamethoxazole exceeded 25 in only one patient. SXT was safe and well-tolerated, except for one patient who had gastrointestinal side-effects after receiving 960 mg of SXT. Additional studies are needed to find the pharmacokinetic and pharmacodynamic targets, and consequently to set the optimal dose, of SXT for MDR-TB treatment.

Multidrug-resistant tuberculosis in Europe, 2010-2011.

Ongoing transmission, high levels of drug resistance, and poor diagnostic

Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients

The use of linezolid for the treatment of multidrug-resistant tuberculosis is limited by dose- and time-dependent toxicity. Recently, we reported a case of pharmacokinetic drug–drug interaction between linezolid and clarithromycin that resulted in increased linezolid exposure. The aim of this prospective pharmacokinetic study is to quantify the effect of clarithromycin on the exposure of linezolid. Subjects were included in an open-label, single-centre, single-arm, fixed-order pharmacokinetic interaction study. All subjects received 300 mg linezolid twice daily during the entire study, consecutively co-administered with 250 mg and 500 mg clarithromycin once daily. Steady-state serum curves of linezolid and clarithromycin were analysed using validated methods, and differences between pharmacokinetic parameters were calculated. Linezolid exposure increased by a median (interquartile range) of 44% (23–102%, p=0.043) after co-administration of 500 mg clarithromycin (n=5) compared to baseline, whereas 250 mg clarithromycin had no statistically significant effect. Co-administration was well tolerated by most patients; none experienced severe adverse effects. One patient reported common toxicity criteria grade 2 gastrointestinal adverse events. In this study, we showed that clarithromycin significantly increased linezolid serum exposure after combining clarithromycin with linezolid in multidrug-resistant tuberculosis patients. The drug–drug interaction is possibly P-glycoprotein-mediated. Due to large interpatient variability, therapeutic drug monitoring is advisable to determine individual effect size. Clarithromycin significantly increased linezolid serum exposure in multidrug-resistant tuberculosis patients http://ow.ly/oYGK1