Tuberculosis transmission between foreign- and native-born populations in the EU/EEA: a systematic review.

Tuberculosis (TB) control programmes of many low TB incidence countries of the European Union/European Economic Area (EU/EEA) perceive challenges in controlling TB due to high numbers of TB in migrants from high-incidence countries. To assess the extent of TB transmission from the foreign-born to the native-born population, we quantitatively investigated the dynamics of TB transmission between these populations in the EU/EEA, using published molecular epidemiological studies. We searched PubMed and EMBASE databases from 1990 to August 2012. We identified 15 studies performed during 1992-2007 covering 12,366 cases, of which median (range) 49.2% (17.7%-86.4%) were foreign-born. The proportion of clustered isolates ranged between 8.5% and 49.1% of the total number of TB cases genotyped and among these, foreign-born cases were equally or more likely to have unique isolates compared to native-born cases. One third of the clusters were "mixed", i.e. composed of foreign- and native-born cases, involving 0-34.2% of all genotyped cases. Cross-transmission among foreign and native populations was bidirectional, with wide differences across studies. This systematic review provides evidence that TB in a foreign-born population does not have a significant influence on TB in the native population in EU/EEA.

Protecting the tuberculosis drug pipeline: stating the case for the rational use of fluoroquinolones.

The use of fluoroquinolones (FQs) to treat lower respiratory tract infections (LTRI) other than tuberculosis (TB) allows selection of FQ-resistant TB when TB is misdiagnosed. This study maps national guidelines on the use of FQs for LRTI in Europe and determines the risk of FQ-resistant TB upon FQ treatment before TB diagnosis. A questionnaire was developed to map existing national LRTI and community-acquired pneumonia (CAP) guidelines. A systematic review and meta-analysis were performed to determine the risk of FQ-resistant TB if prescribed FQs prior to TB diagnosis. 15 (80%) out of 24 responding European Respiratory Society national delegates reported having national LRTI management guidelines, seven including recommendations on FQ use and one recommending FQs as the first-choice drug. 18 out of 24 countries had national CAP management guidelines, two recommending FQ as the drug of choice. Six studies investigating FQ exposure and the risk of FQ-resistant TB were analysed. TB patients had a three-fold higher risk of having FQ-resistant TB when prescribed FQs before TB diagnosis, compared to non FQ-exposed patients (OR 2.81, 95% CI 1.47-5.39). Although the majority of European countries hold national LRTI/CAP guidelines, our results suggest that a risk of developing FQ resistance exists. Further strengthening of, and adherence to, guidelines is needed to ensure rational use of FQs.

Multidrug resistance after inappropriate tuberculosis treatment: a meta-analysis.

We conducted a systematic review and meta-analysis to assess the evidence for the postulation that inappropriate tuberculosis (TB) regimens are a risk for development of multidrug-resistant (MDR)-TB. MEDLINE, EMBASE and other databases were searched for relevant articles in January 2011. Cohort studies including TB patients who received treatment were selected and data on treatment regimen, drug susceptibility testing results and genotyping results before treatment and at failure or relapse were abstracted from the articles. Four studies were included in the systematic review and two were included in the meta-analysis. In these two studies the risk of developing MDR-TB in patients who failed treatment and used an inappropriate treatment regimen was increased 27-fold (RR 26.7, 95% CI 5.0-141.7) when compared with individuals who received an appropriate treatment regimen. This review provides evidence that supports the general opinion that the development of MDR-TB can be caused by inadequate treatment, given the drug susceptibility pattern of the Mycobacterium tuberculosis bacilli. It should be noted that only two studies provided data for the meta-analysis. The information can be used to advocate for adequate treatment for patients based on drug resistance profiles.

Knowledge of tuberculosis-treatment prescription of health workers: a systematic review.

Treating tuberculosis (TB) patients with inappropriate treatment regimens can lead to treatment failure and, thus, patients who have not been cured and/or to the development of (multi)-drug resistance. A systematic review was performed to assess the knowledge of appropriate TB drug regimens among all categories of healthcare workers (HCWs). In January 2011, MEDLINE, EMBASE and other databases were searched for relevant articles. Observational studies published as of the year 2000 that assessed HCW knowledge of TB treatment were selected. A treatment regimen, drug dosage or treatment duration was considered inappropriate if it was not recommended by national guidelines or by the World Health Organization (WHO). Of 1,896 studies, 31 were included from 14 different countries. No study was performed in Europe. In all studies, HCWs with inappropriate knowledge of treatment regimens (8-100%) or treatment duration (5-99%) were observed. The few studies providing detailed data showed that HCWs mainly reported giving treatment regimens with too many drugs and for too long. Knowledge of appropriate doses was also insufficient in most studies. The available studies show that there is a lack of knowledge of national or international TB treatment guidelines and recommendations. Generalisation of the findings to other settings and countries should be done with caution.

In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor.

The diarylquinoline R207910 is in clinical development for tuberculosis treatment. The MIC(50) for 41 drug-susceptible and 44 multidrug-resistant Mycobacterium tuberculosis clinical isolates was 0.032 microg/ml. Out of 20 additional mycobacterial species, three were found to be naturally resistant to R207910 and were shown to exhibit a polymorphism in their atpE genes.

Resistance levels and rpoB gene mutations among in vitro-selected rifampin-resistant Mycobacterium tuberculosis mutants.

The distribution and resistance levels of 189 in vitro-selected rifampin-resistant Mycobacterium tuberculosis mutants of Beijing and other genotypes were determined. Apart from a higher amount of codon 522 point mutations and large deletions, a spread of mutations similar to that reported for clinical isolates was seen. Most mutations were correlated with high-level resistance; a lower level, or a MIC of <16 mg/liter, was associated with codon 522 mutations. Multiple mutations were detected in two Beijing mutants.

A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.

The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.