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)

Drug-resistance in M. tuberculosis & the characterisation of a new anti-tuberculosis drug-candidate

The occurrence of multidrug-resistant (MDR) tuberculosis (TB) has been increasing at alarming levels globally, and the spread of extensively drug-resistant (XDR) M. tuberculosis is threatening the control of tuberculosis. Understanding the molecular mechanisms behind resistance is an important tool in minimising and preventing its spread, as faster diagnostic methods can de developed and treatment guidelines be optimised. There is also an urgent need to find and develop effective drugs that simplify and shorten the existing treatment regimen, as well as being effective against all forms of TB. The current thesis presents the characterisation of in vitro-resistance to rifampicin (RIF), as well as the pre-clinical characterisation of a promising new anti-TB drug candidate. In Paper I we investigated RIF-resistance mutations within the rpoB gene of in vitro-selected resistant mutants. The array and frequency of mutations, as well as the resistance-levels found in these mutants were similar to those reported for RIF-resistant clinical isolates. Furthermore, we saw that mutants of the Beijing genotype, a family of strains known to be spreading globally and commonly associated with MDR, did not portray a different span of resistance mutations or resistance-level. Papers II-IV present the pre-clinical characterisation of R207910. R207910 is a new anti-TB drug candidate identified for its high Mycobacterial specificity. This Diarylquinoline, a new class of compounds, was shown to have a strong inhibitory effect on both drug-susceptible and MDR M. tuberculosis (Minimum Inhibitory Concentration 0.03μg/ml). In combination with the standard combinatorial TB-treatment regimen, R207910 further had an equal, if not stronger, bactericidal activity in mice than the standard regimen alone. In vitro studies showed that resistance occurs through mutations in the bacilli s ATP synthase indicating that the compound targets a unique site; the bacilli s energy-producing ATP synthase. Resistance to R207910 occurred at a relatively slow rate (approx 10-8 mutations per cell generation) and this spontaneous acquisition of resistance was prevented at an R207910-concentration of 3 mg/ml, a level deemed attainable within humans without causing adverse effects. R207910 shows the potential of shortening and simplifying the treatment of both DS and MDR-TB. Furthermore, having characterised the dynamics of resistance development to the compound before it reaches clinical use, treatment doses and guidelines can be established that will cure TB-patients as well as prolong, and hopefully prevent, the emergence of clinical R207910-resistance

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

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 μg/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

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 profile

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 Fa-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 Fa-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 Fa-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 Fa-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 FQ